Reverse-repurposing--Potential-utility-of-cancer-d

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Reverse repurposing: Potential utility
of cancer drugs in nonmalignant illnesses
Mina Nikanjam,1,6,* Kaitlyn Wells,2,6 Shumei Kato,1 Jacob J. Adashek,3 Shanna Block,2
and Razelle Kurzrock4,5,*
SUMMARY
Growth and immune process dysregulation can result in both cancer
and nonmalignant disease (hereditary or acquired, with and without
predisposition to malignancy). Moreover, perhaps unexpectedly,
many nonmalignant illnesses harbor genomic alterations indistin-
guishable from druggable oncogenic drivers. Therefore, targeted
compounds used successfully to treat cancer may have therapeutic
potential for nonmalignant conditions harboring the same target.
MEK, PI3K/AKT/mTOR, fibroblast growth factor receptor (FGFR),
and NRG1/ERBB pathway genes have all been implicated in both
cancer and noncancerous conditions, and several cognate antago-
nists, as well as Bruton’s tyrosine kinase inhibitors, JAK inhibitors,
and CD20-directed antibodies, have established or theoretical ther-
apeutic potential to bridge cancer and benign diseases. Intriguingly,
pharmacologically tractable cancer drivers characterize a wide spec-
trum of disorders without malignant potential, including but not
limited to Alzheimer’s disease and a variety of other neurodegener-
ative conditions, rheumatoid arthritis, achondroplastic dwarfism,
and endometriosis. Expanded repositioning of oncology agents in
order to benefit benign but serious medical illnesses is warranted.
INTRODUCTION
Aberrant proliferative and immune processes can result in the development of can-
cer and can also lead to nonmalignant conditions. Surprisingly, molecular interroga-
tion of tissue affected by nonmalignant illnesses, which may be congenital or ac-
quired, and premalignant or not associated with malignancy, at times uncover
‘‘oncogenic’’ driver genomic alterations. Oncogenic drivers are alterations in genes
that encode signals crucial for maintaining normal cellular growth and survival; these
alterations have a confirmed role in the initiation and/or progression of cancer. 1Division of Hematology-Oncology, University of
Importantly, some of these oncogenic driver aberrations are now druggable in the California, San Diego, La Jolla, CA, USA
2Department of Pharmacy, University of
context of cancer, often with impressive responses. The natural question that arises
California, San Diego, La Jolla, CA, USA
is whether drugs developed for targeting specific molecular abnormalities in cancer 3Department of Oncology, Johns Hopkins
could be repurposed to treat nonmalignant illnesses that harbor the same or similar University, Baltimore, MD, USA
molecular aberrations. 4Divisionof Hematology-Oncology, Medical
College of Wisconsin Cancer Center, Milwaukee,
WI, USA
Although there remains a lack of adequate cross-fertilization between fields, some
5WIN Consortium, Chevilly-Larue, France
successes in reverse repurposing, that is repurposing drugs from the cancer field
6These authors contributed equally
to nonmalignant conditions, have already been reported. For instance, MEK
*Correspondence:
pathway activation due to somatic mutations in KRAS or other MEK pathway genes mnikanjam@health.ucsd.edu (M.N.),
is frequently found in malignancy, being discerned in over 30% of tumors.1,2 rkurzrock@mcw.edu (R.K.)
Notably, excessive activation of the MEK pathway has also been observed in https://doi.org/10.1016/j.medj.2024.04.008
Med 5, 689–717, July 12, 2024 ª 2024 Elsevier Inc. All rights reserved. 689
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Review
arteriovenous malformations (AVM), including those in the brain, a nonmalignant but

difficult-to-manage condition; this activation can be due to somatic activating KRAS
mutations, though other genes in the pathway may also be aberrant.3 Intriguingly,
Lekwuttikarn et al. reported that, in a child with an extracranial AVM and a somatic
MAP2K1 mutation (also known to activate the MEK pathway), administration of
the MEK inhibitor trametinib, which is approved for cancers such as melanoma
harboring MEK pathway aberrations, resulted in reduced size of the malformation
and lightening of color.4 Similarly, Nicholson and colleagues reported successful
management of an AVM with trametinib in a teenager with capillary-malformation
AVM syndrome and cardiac compromise.5
Other important examples of repurposing drugs relate to medications targeting

PI3K/AKT/mTOR pathway aberrations. Genes in this pathway are frequently
mutated in cancer, being seen in 38% of malignancies.6 There are several drugs
that are approved by the Food and Drug Administration (FDA) for various malig-
nancies, including PIK3CA inhibitors (e.g., alpelisib for breast cancer), AKT inhibitors
(e.g., capivasertib for breast cancer), and mammalian target of rapamycin (mTOR) in-
hibitors (e.g., everolimus and temsirolimus for breast and renal cancers).7 Of interest
in this regard, PIK3CA-related overgrowth spectrum (PROS) includes a group of
congenital disorders that lead to segmental/asymmetric overgrowth of various
body parts (brain, limbs, trunk, and face) and anomalies in blood and lymphatic el-
ements as well as in other tissues due to PIK3CA mutations.8 PROS are caused by
heterozygous mosaic postzygotic (or, rarely, constitutional) activating pathogenic
variants in PIK3CA. Surprisingly, PROS do not predispose to cancers typically related
to PIK3CA pathway alterations.9 In 2022, the FDA approved the PIK3CA inhibitor al-
pelisib (as mentioned, also approved for breast cancers bearing PIK3CA mutations)
for children with PROS, as it combats some of the growth anomalies typical of the
disorder.10
There are many other similar examples of aberrations typical of cancer that can cause
nonmalignant conditions. For instance, TP53 mutations are detected in 40% of
metastatic cancers and are perhaps the most common tumor suppressor anomaly
in cancer.11 Of interest, TP53 mutations contribute to the overexpression of
interleukin-6 (IL-6) in renal cell carcinoma via activation of downstream signaling
pathways.12 Increased IL-6 signaling can also promote chronic inflammatory and
autoimmune disease.13,14 Moreover, the synovium from patients with rheumatoid
arthritis may bear pathogenic TP53 mutations (without any cancer predisposition),15
which may explain why IL-6 levels are elevated in this nonmalignant inflammatory
disorder and may also account for the effectiveness of the FDA-approved anti-IL6
therapy (tocilizumab; IL-6 receptor antibody) for rheumatoid arthritis.16
Given that malignant and nonmalignant conditions can have similar pathways and
genomic drivers, several groups have begun to expand investigation into repurpos-
ing drugs from nonmalignant to malignant conditions and vice versa.17–20 Herein, we
review the spectrum of gene and pathway alterations found in cancer that can also
affect nonmalignant disease and the agents that have been repositioned or that
could be repositioned based on their mechanism of action (Tables 1, 2,
and 3).4,12,13,17,18,21–71 Drugs used for adult malignancy/oncology indications
were identified on the Chemocare database (https://chemocare.com/) and the Na-
tional Comprehensive Cancer Network Drugs & Biologics Compendium (https://
www.nccn.org/professionals/drug_compendium/content/). The FDA-approved in-
dications for each drug were checked using UpToDate (http://www.uptodate.com)
and Micromedex (https://www.micromedexsolutions.com) and confirmed with
690 Med 5, 689–717, July 12, 2024

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Table 1. Examples of nonmalignant germline and acquired medical nonmalignant or premalignant conditions with alterations in molecular pathways also implicated in malignancies
Benign or Targeted therapy for Approximate Examples of
premalignant Hereditary germline nonmalignant conditions frequency of pathway-targeted
Gene condition conditions or somatic with mutations in altered gene in therapy approved
altered (alteration)17,18 mosaicism (alteration)17,18 ‘‘oncogenic drivers’’17,18 malignancies21,22 for malignancya
AKT seborrheic Proteus syndrome clinical data: miransertib (AKT 2% of cancers capivasertib
keratoses inhibitor) for Proteus syndrome23 have AKT1 (AKT inhibitor)
theoretical/preclinical: alterations
Akt inhibitors A-443654
or GSK690693 for
seborrheic keratoses24
ALK inflammatory – approved: crizotinib 3% of cancers alectinib, brigatinib,
myofibroblastic clinical data: alectinib, have ALK ceritinib, crizotinib,
tumor (ranges brigatinib, ceritinib, and alterations and lorlatinib26
from benign lorlatinib for inflammatory
to malignant) myofibroblastic tumor 25
APC – FAP theoretical/preclinical: 11% of cancers –
sorafenib or other Wnt have APC
pathway inhibitors for FAP 27 alterations
ARAF – CCLA clinical data: sirolimus 1.5% of cancers –
or trametinib have ARAF
alterations
BRAF melanocytic CFC clinical data: MEK inhibitors 6% of cancers binimetinib,
nevi (majority Noonan syndrome including trametinib and have BRAF cobimetinib,
have pathogenic mirdametinib for alterations selumetinib,
BRAF V600E Noonan syndrome 28 and trametinib
mutations despite theoretical/preclinical: (MEK inhibitors)
negligible rates BRAF and/or MEK dabrafenib,
of transformation inhibitors for CFC29 encorafenib,
to melanoma) and vemurafenib
(BRAF inhibitors)
ERBB4/NRG130 – ALS1930 ERBB4 (ALS19) are inactivating 3% of cancers –
NRG1 may be upregulated in amyotrophic lateral sclerosis have ERBB4
in ALS, Alzheimer’s disease, but may cause upregulation alterations
and schizophrenia of the ligand NRG1 and hence <0.5% of cancers
upregulation of other ERBB have NRG1
family members, which might alterations
be counteracted by
pan-ERBB inhibitors30
FGFR1 – FGFR1 gain of function: FGFR1 mutations in Hartsfield 4% of cancers pan-FGFR inhibitors
Kallman syndrome and syndrome are inactivating have FGFR1 alterations including erdafitinib,
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Pfeiffer syndrome and would thus make futibatinib,

FGFR1 loss of function: pan-FGFR inhibitors ineffective31 pemigatinib,
Hartsfield syndrome theoretical: FGFR inhibitors and lenvatinib
such as erdaftinib, pemigatinib,
infigratinib, and futibatinib
for Pfeiffer syndrome
FGFR2 KEN FGFR2 gain of function: theoretical: FGFR inhibitors 2% of cancers pan-FGFR inhibitors
craniosynostosis syndromes, such as erdaftinib, pemigatinib, have FGFR2 alterations including erdafitinib,
Apert syndrome, and futibatinib for futibatinib,
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Beare-Stevenson cutis syndromes with gain-of-function pemigatinib, and
gyrata syndrome, and FGFR alterations lenvatinib
Pfeiffer syndrome
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Table 1. Continued
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FGFR3 seborrheic FGFR3 gain of function: theoretical: FGFR inhibitors 2.5% of cancers pan-FGFR inhibitors
keratosis and achondroplasia, such as erdafitinib, futibatinib, have FGFR3 alterations including erdafitinib,
epidermal nevi hypochrondroplasia, Muenke pemigatinib, and infigratinib for futibatinib,
syndrome, and achondroplasia, thanatophoric pemigatinib, and
thanatophoric dysplasia dysplasia, seborrheic keratosis, lenvatinib
FGFR3 loss of function: and epidermal nevi32
LADD syndrome infigratinib is currently
in clinical trials for
achondroplasia33
FGFR3 mutations in LADD lead
to reduced activity and would
thus make pan-FGFR
inhibitors ineffective
GNAQ – Sturge-Weber syndrome theoretical: MEK inhibitors 0.7% of cancers –
such as trametinib for have GNAQ alterations
Sturge-Weber syndrome
GNAS – McCune-Albright syndrome theoretical: MEK inhibitors 3.2% of cancers –
such as trametinib for have a GNAS alterations
McCune-Albright syndrome 34
HRAS – RASopathies35 theoretical: MEK inhibitors 0.9% of cancers –
such as trametinib for have HRAS alterations
Costello syndrome
IDH2 – D2HGA clinical data: enasidenib 1.5% of cancers enasidenib
for D2HGA36 have IDH2 alterations
IGFR thyroid – approved: teprotumumab 2.5% of cancers –
eye disease37 (R1507) (IGFR antibody) have IGF1R alterations
for thyroid eye disease38 some alterations, such as the
EWS-FLI fusion in Ewing sarcoma,
may activate the IGFR axis, perhaps
explaining responses seen
using IGFR antibodies in
Ewing sarcoma39,40
JAK3 – SCID JAK3 mutations in SCID are 2% of cancers have –
inactivating and would thus JAK3 alterations
make JAK inhibitors ineffective
KRAS arteriovenous RASopathies clinical data: trametinib for AVM4 16% of cancers adagrasib and sotorasib
malformation theoretical/preclinical/clinical: MEK have KRAS alterations (approved for KRAS
(AVM) in brain, inhibitors such as trametinib in AVM other genes in the G12C mutations)
endometriosis, in brain and endometriosis 42,43 and MEK pathway may the MEK inhibitors
and Alzeheimer’s BRAF and/or MEK also be aberrant in trametinib, cobimetinib,
disease41 inhibitors for RASopathies29 some of these selumetinib, and
reports of reversal of severe hypertrophic conditions—for example, binimetinib are also
cardiomyopathy and chylous effusions MAP2K1 may be altered approved but for cancers
in children with Noonan syndrome in AVM and in cancer4,47 harboring MEK pathway
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treated with the MEK alterations in genes such
inhibitor trametinib44–46 as BRAF and NF1
MAP2K1 arteriovenous – clinical data: MEK 1% of cancers –
malformations inhibitor trametinib for AVM4 have MAP2K1 alterations
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Table 1. Continued
MET – DFNB97 hearing MET mutation in DFNB97 2.5% of cancers –
loss (deafness, hearing loss is inactivating have MET alterations
autosomal recessive) and would thus make
MET inhibitors ineffective
NF1 – NF1 approved (FDA): selumetinib 6.5% of cancers –
clinical data: trametinib for NF148 have NF1 alterations
NF2 – NF2 clinical data: temsirolimus 2% of cancers –
(mTor inhibitor) for NF249 have NF2 alterations
altered NF2 may
activate the
PI3K/Akt/mTor pathway 50,51
NRAS giant congenital – theoretical/preclinical/clinical: 3% of cancers –
melanocytic BRAF inhibitors such as have NRAS alterations
nevi and vemurafenib and MEK inhibitors
melanocytic nevi such as binimetinib and
trametinib for giant congenital
melanocytic nevi52–54
PI3K-related seborrheic keratosis, PROS and APDS approved: alpelisib (PIK3CA 13% of cancers multiple approved
genes endometriosis, and (caused by mutations inhibitor also approved for have PIK3CA alterations PI3K/Akt/mTor pathway
Alzheimer’s disease41 in PIK3CD or PIK3R1 breast cancer) for PROS 38% of cancers inhibitors including
genes that encode and leniolisib (selective have genomic alterations alpelisib (PIK3CA
the protein PI3Kd) PI3Kd inhibitor) for APDS in the PI3K pathway inhibitor), capivasertib
clinical data: sirolimus (AKT inhibitor), and
for PROS everolimus,
theoretical: PIK3CA temsirolimus,
inhibitors such as alpelisib nab-sirolimus,
for seborrheic keratosis and sirolimus
and endometriosis (mTor inhibitors)
PTEN – hamartoma tumor clinical data: mTOR inhibitors 7% of cancers –
syndrome (includes such as everolimus in have PTEN alterations
Cowden syndrome)55 hamartoma tumor syndrome56 PTEN alterations are
usually loss of function,
which in turn activates
the PI3K/Akt/mTor pathway
RET – Hirschsprung disease RET mutations in Hirschsprung 2.5% of cancers –
disease are generally inactivating, have activating RET alterations
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while RET alterations in cancers

are generally activating—therefore,
RET inhibitors for cancer
would not be effective for
Hirschsprung disease
STK11 – Peutz-Jegher syndrome 57 clinical data: mTOR inhibitors 3% of cancers –
such as everolimus for have STK11 alterations
Peutz-Jegher syndrome58
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Table 1. Continued
TP53 rheumatoid Li-Fraumeni syndrome theoretical: anti-angiogenics 40% of cancers –
arthritis such as bevacizumab for have TP53 alterations
synovium and rheumatoid arthritis synovitis
aging esophagus and Li-Fraumeni syndrome,
since TP53 mutations
upregulate the VEGF/VEGFR
axis and correlate with
response to VEGF/VEGFR
inhibitors in cancer59–61
mutant TP53 upregulates
IL-6, so inhibitors of IL-6
are approved for rheumatoid
arthritis and for
Castleman disease12,62,63
TSC1/TSC2 – tuberous sclerosis approved: everolimus 2% of cancers –
complex55 and sirolimus for have TSC1 alterations
tuberous sclerosis 3.5% of cancers
complex seizures have TSC2 alterations
TSC1 and TSC2
alterations activate
mTor signals
ALK, anaplastic lymphoma kinase; ALS19, amyotrophic lateral sclerosis subtype 19; APC, adenomatous polyposis coli; APDS, activated PI3K delta syndrome; AVM, arteriovenous malformation; CCLA, central
conducting lymphatic anomaly; CFC, cardiofaciocutaneous syndrome; D2HGA, D-2-hydroxygluaric aciduria; FAP, familial adenomatous polyposis; FGFR, fibroblast growth factor receptor; IDH2, isocitrate
dehydrogenase 2; IGFR, insulin-like growth factor receptor; IL-6, interleukin-6; JAK, Janus kinase; KEN, keratinocytic epidermal nevus; LADD, lacrimo-auriculo-dento-digital syndrome; mTOR, mammalian
target of rapamycin; NF1, neurofibromatosis type 1; NF2, neurofibromatosis type 2; PI3Kd, protein called phosphoinositide-3 kinase d; PROS, PIK3CA-related overgrowth spectrum; SCID, severe combined
immunodeficiency; STK11, serine/threonine kinase 11; TP53, tumor protein P53.
a
FDALabel (database online): Drug Product Labeling. US Food & Drug Administration. https://nctr-crs.fda.gov/fdalabel/ui/search.
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Table 2. Examples of FDA approvals for malignant and nonmalignant diseases by therapeutic classa
Drug(s) approved in nonmalignant
Target Drug(s) approved in malignant conditions conditions Comments Mechanism in nonmalignant conditions
BTK acalabrutinib: CLL/SLL, MCL ibrutinib: chronic GVHD – inhibition of BTK that is hyperactivated
inhibitors ibrutinib: CLL/SLL, in chronic GVHD B cells64
Waldenström macroglobulinemia
pirtobrutinib: MCL
zanubrutinib: CLL/SLL, MCL, MZL,
Waldenström macroglobulinemia
CD20- ibritumomab tiuxetan: NHL ocrelizumab: MS – depletion of the pathogenic, self-reactive
directed obinutuzumab: CLL, FL ofatumumab: MS B cells found in autoimmune conditions65
antibodies ofatumumab: CLL rituximab: GPA,
rituximab: CLL, NHL microscopic polyangiitis,
pemphigus vulgaris,
rheumatoid arthritis
ublituximab: MS
FGFR erdafitinib: urothelial cancer with nintedanib: idiopathic there are several the FGFR pathway is critical for processes
inhibitors susceptible FGFR2 or FGFR3 pulmonary fibrosis, other multikinase active in fibrosis such as fibroblast
alterations progressive chronic inhibitors that block proliferation, migration, and differentiation
futibatinib: cholangiocarcinoma fibrosing ILD, systemic FGFR (e.g., lenvatinib) as well as the secretion of extracellular
with FGFR2 fusion or other sclerosis-associated ILD matrix66
rearrangement
pemigatinib: cholangiocarcinoma
with FGFR2 fusion or other
rearrangement, myeloid/lymphoid
neoplasm with FGFR1 rearrangement
GnRH goserelin: breast cancer, goserelin: endometrial thinning – hormone suppression limits
agonists prostate cancer agent prior to endometrial ablation endometrial growth
histrelin: prostate cancer for dysfunctional uterine bleeding,
leuprolide: prostate cancer endometriosis
triptorelin: prostate cancer histrelin: central precocious puberty
leuprolide: central precocious puberty,
endometriosis, uterine fibroids
nafarelin: central precocious
puberty, endometriosis
triptorelin: central precocious puberty
GnRH degarelix: prostate cancer cetrorelix: controlled ovarian – hormone suppression limits
antagonists relugolix: prostate cancer stimulation endometrial growth or can help
elagolix: endometriosis with ovarian stimulation
ganirelix: controlled ovarian
stimulation
IL-6 siltuximab: Castleman diseaseb sarilumab: polymyalgia – IL-6 signaling can lead to chronic
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inhibitors rheumatica, rheumatoid arthritis inflammatory and autoimmune disease13

satralizumab: neuromyelitis
optica spectrum disorder
tocilizumab: CAR T cell-associated
CRS, COVID-19, giant cell arteritis,
rheumatoid arthritis, systemic juvenile
idiopathic arthritis, systemic
sclerosis-associated ILD
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Table 2. Continued
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Drug(s) approved in nonmalignant
Target Drug(s) approved in malignant conditions conditions Comments Mechanism in nonmalignant conditions
JAK fedratinib: myelofibrosis abrocitinib: atopic dermatitis – JAK pathway activation can lead to
inhibitors momelotinib: myelofibrosis baricitinib: alopecia areata, COVID-19, autoimmunity through T cell
pacritinib: myelofibrosis rheumatoid arthritis differentiation, lymphocyte effector
ruxolitinib: myelofibrosis, PV deucravacitinib: plaque psoriasis function, and macrophage activation67
ritlecitinib: alopecia areata
ruxolitinib: atopic dermatitis (topical),
GVHD, nonsegmental vitiligo (topical)
tofacitinib: ankylosing spondylitis, ju-
venile arthritis, psoriatic arthritis, rheu-
matoid arthritis, ulcerative colitis
upadacitinib: ankylosing spondylitis,
atopic dermatitis, Crohn’s disease,
psoriatic arthritis, rheumatoid arthritis,
spondyloarthritis, ulcerative colitis
MEK binimetinib: melanoma with BRAF selumetinib: neurofibromatosis type 1 – tumor growth and neurofibromatosis
inhibitors V600E or V600K mutation, NSCLC type 1 is driven by overactivation
with BRAF V600E mutation of RAS pathway68
cobimetinib: histiocytic neoplasms,
melanoma with BRAF V600E or
V600K mutation
trametinib: anaplastic thyroid
cancer/glioma/NSCLC/solid
tumors with BRAF V600E
mutation, melanoma with
BRAF V600E or V600K mutation
mTOR everolimus: breast cancer, NET, everolimus: liver transplant, renal – tuberous sclerosis is associated with
inhibitors RCC, TSC-associated subependymal transplant, TSC-associated mTOR pathway overactivation69;
giant cell astrocytoma partial-onset seizures, mTOR inhibition blocks T lymphocyte
nab-sirolimus: PEComas TSC-associated renal angiomyolipoma activation and proliferation induced
temsirolimus: RCC sirolimus: facial angiofibroma by antigen and cytokine stimulation,
associated with TSC (topical), which leads to immunosuppression
kidney transplant, for transplant applications70
lymphangioleiomyomatosis
PI3K alpelisib: PIK3CA-mutated alpelisib: PROS – dysregulation of PI3K pathway
pathway breast cancer leniolisib: activated PI3K leads to cell proliferation71
inhibitors delta syndrome
BTK, Bruton’s tyrosine kinase; CLL, chronic lymphocytic leukemia; CAR, chimeric antigen receptor; COVID-19, coronavirus disease 2019; CRS, cytokine release syndrome; FGFR, fibroblast growth factor re-
ceptor; FL, follicular lymphoma; GnRH, gonadotropin-releasing hormone; GPA, granulomatosis with polyangiitis; GVHD, graft-versus-host disease; IL-6, interleukin-6; JAK, Janus kinase; ILD, interstitial lung
disease; LH, luteinizing hormone; MCL, mantle cell lymphoma; MEK, mitogen-activated extracellular kinase; mTOR, mammalian target of rapamycin; MS, multiple sclerosis; MZL, marginal zone lymphoma;
NET, neuroendocrine tumor; NHL, non-Hodgkin’s lymphoma; NSCLC, non-small cell lung cancer; PI3K, phosphatidylinositol 3-kinase; PEComa, perivascular epithelioid cell tumor; PIK3CA, phosphatidylino-
sitol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; PROS, PIK3CA-related overgrowth spectrum; PV, polycythemia vera; RCC, renal cell carcinoma; SLL, small lymphocytic lymphoma; TSC, tuberous scle-
rosis complex.
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a
b
Whether or not Castleman disease is a cancer is a matter of debate.
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Table 3. Examples of therapeutics with FDA-approved malignant and nonmalignant indicationsa
Nonmalignant/
Drug Class/mechanism Malignant indications premalignant indications Initial FDA indicationb Comments
5-fluorouracil pyrimidine nucleoside breast cancer, colorectal actinic keratosis (topical) malignant: colorectal –
analog cancer, gastric cancer, cancer (1962)c
pancreatic cancer,
superficial basal cell
carcinoma (topical)
Alemtuzumab CD52-directed B cell CLL multiple sclerosis malignant: B cell CLL (2001) –
monoclonal antibody
All-trans retinoic acid retinoid APL acne vulgaris (topical), nonmalignant: acne –
photoaging (topical) vulgaris (1971)c
Alpelisib PI3K kinase inhibitor breast cancer PROS malignant: breast –
cancer (2019)
Cladribine purine nucleoside analog hairy cell leukemia multiple sclerosis malignant: hairy cell –
leukemia (1993)
Crizotinib multi-tyrosine kinase NSCLC, anaplastic large inflammatory malignant: NSCLC (2011) –
inhibitor cell lymphoma myofibroblastic tumor
Daratumumab CD38-directed monoclonal multiple myeloma light chain malignant: multiple while amyloidosis may be associated with
and hyaluronidase antibody amyloidosis myeloma (2020) blood cancers such as multiple myeloma, it is
not in and of itself a malignancy
Denosumab RANKL-directed monoclonal giant cell tumor of bone hypercalcemia of nonmalignant: –
antibody malignancy, osteoporosis (2010)
osteoporosis,
prevention of
skeletal-related
events
Dexamethasone corticosteroid leukemias, lymphomas, allergic states, undefined (1958)c labeled indications are not well defined;
multiple myeloma dermatologic general classes of approved indications are
diseases, endocrine listed here
disorders,
gastrointestinal
diseases,
hematologic
disorders
Eflornithine ornithine decarboxylase high-risk neuroblastoma hirsutism (topical), nonmalignant: CNS –
inhibitor West African trypanosomiasis (1990)
trypanosomiasis
with CNS involvement
Everolimus mTOR inhibitor breast cancer, PNET, liver transplant, malignant: renal cell –
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renal cell carcinoma, renal angiomyolipoma carcinoma (2009)

subependymal giant with TSC, renal
cell astrocytoma transplant,
associated with TSC TSC-associated
partial-onset seizures
Fluoxymesterone synthetic androgen breast cancer delayed puberty, undefined (1956)c manufacturing discontinued in the United
hypogonadism States; however, remains FDA approved
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Table 3. Continued
Nonmalignant/
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Goserelin GnRH agonist prostate cancer, endometrial thinning malignant: prostate –
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breast cancer agent prior to cancer (1989)
endometrial
ablation for
dysfunctional
uterine bleeding,
endometriosis
Histrelin GnRH agonist prostate cancer central precocious nonmalignant: central –
puberty precocious puberty (1991)
Hydrocortisone corticosteroid leukemias and allergic states, undefined (1951)c indicated in numerous conditions; general
lymphomas collagen diseases, classes of approved indications are listed here
dermatologic
diseases, edematous
states, endocrine
disorders,
gastrointestinal
diseases,
hematologic
disorders, ophthalmic
diseases, respiratory
diseases, rheumatic
disorders
Hydroxyurea antimetabolite CML, head and neck cancer sickle cell anemia malignant (1967)c –
Ibrutinib Bruton’s tyrosine kinase CLL/SLL, Waldenström GVHD malignant: mantle cell indication for mantle cell lymphoma removed
inhibitor macroglobulinemia lymphoma (2013) in 2023
Imiquimod Toll-like receptor 7 agonist basal cell carcinoma actinic keratosis, nonmalignant: genital –
genital warts warts (1997)
Interferon alfa-2b; interferon follicular lymphoma, genital warts, malignant: hairy cell manufacturing of interferon alfa-2b was
ropeginterferon hairy cell leukemia, hepatitis B, leukemia (1986) discontinued in the United States; however,
alfa-2b Kaposi sarcoma, hepatitis C remains FDA approved
melanoma,
polycythemia vera
Lanreotide somatostatin analog carcinoid syndrome, acromegaly nonmalignant: –
gastroenteropancreatic NET acromegaly (2007)
Leuprolide GnRH agonist prostate cancer central precocious malignant: prostate –
puberty, endometriosis, cancer (1985)
uterine fibroids
Megestrol acetate progestin breast cancer, AIDS-associated malignant: endometrial –
endometrial cancer anorexia/cachexia cancer (1971)b
Methotrexate folate antimetabolite ALL, breast cancer, polyarticular juvenile malignant: acute –
head and neck cancer, idiopathic arthritis, leukemia (1953)c
lung cancer, meningeal psoriasis, rheumatoid
leukemia, mycosis arthritis
fungoides, NHL,
osteosarcoma,
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gestational trophoblastic
neoplasia
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Table 3. Continued
Nonmalignant/
Methylprednisolone corticosteroid leukemias and allergic states, collagen undefined (1957)c labeled indications are not well defined;
lymphomas disorders, dermatologic general classes of approved indications are
diseases, endocrine listed here
disorders, gastrointestinal
diseases, benign
hematologic disorders,
ophthalmic diseases,
renal diseases,
respiratory diseases,
rheumatic disorders
Mitomycin anticancer antibiotic gastric cancer, adjunct to glaucoma malignant: gastric and –
pancreatic cancer, surgery (ophthalmic) pancreatic cancers (1974)c
urothelial cancer
(ureteral gel)
Mitoxantrone anthracycline AML, prostate cancer multiple sclerosis malignant: AML (1987) –
Octreotide somatostatin analog carcinoid tumors, acromegaly malignant: carcinoid –
VIPoma tumors and VIPomas (1988)
Ofatumumab CD20-directed CLL multiple sclerosis malignant: CLL (2009) –
monoclonal antibody
Prednisone corticosteroid leukemias and allergic states, undefined (1955)c indicated in numerous conditions; general
lymphomas in adults collagen diseases, classes of approved indications are listed here
dermatologic diseases,
edematous states,
endocrine disorders,
gastrointestinal diseases,
hematologic disorders,
nervous system disorders,
ophthalmic diseases,
respiratory diseases,
rheumatic disorders
Prednisolone corticosteroid leukemias and allergic states, undefined (1955)c indicated in numerous conditions; general
lymphomas in adults collagen diseases, classes of approved indications are listed here
dermatologic diseases,
edematous states,
endocrine disorders,
gastrointestinal diseases,
benign hematologic
disorders, ophthalmic
Med 5, 689–717, July 12, 2024
diseases, respiratory
diseases, rheumatic
disorders
Raloxifene selective estrogen risk reduction for osteoporosis nonmalignant: –
receptor modulator invasive breast cancer osteoporosis
prevention (1997)
Rituximab CD20-directed CLL, NHL GPA, microscopic malignant: –
monoclonal antibody polyangiitis, pemphigus NHL (1997)
ll
vulgaris, rheumatoid arthritis
699
700
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Table 3. Continued
Nonmalignant/
Ruxolitinib Janus kinase inhibitor myelofibrosis, atopic dermatitis malignant: –
polycythemia vera (topical), nonsegmental myelofibrosis
vitiligo (topical), GVHD (2011)
Sirolimus; sirolimus, mTOR inhibitor PEComa facial angiofibroma nonmalignant: kidney –
albumin bound associated with TSC transplant (1999)
(topical), kidney
transplant,
lymphangioleiomyomatosis
Thalidomide immunomodulatory drug multiple myeloma erythema nodosum nonmalignant: erythema –
leprosum nodosum leprosum (1998)
Triptorelin GnRH agonist prostate cancer central precocious puberty malignant: prostate –
cancer (2000)
AIDS, acquired immunodeficiency syndrome; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myeloid
leukemia; CNS, central nervous system; GnRH, gonadotropin-releasing hormone agonist; GPA, granulomatosis with polyangiitis; GVHD, graft-versus-host disease; mTOR, mammalian target of rapamycin;
NET, neuroendocrine tumor; NHL, non-Hodgkin’s lymphoma; NSCLC, non-small cell lung cancer; PEComa, malignant perivascular epithelioid cell tumor; PNET, neuroendocrine tumor of pancreatic origin;
PROS, PIK3CA-related overgrowth spectrum; RANKL, receptor activator of nuclear factor-kB ligand; SLL, small lymphocytic lymphoma; TSC, tuberous sclerosis complex; VIPomas, vasoactive intestinal pep-
tide-secreting tumors.
a
b
See also Table S1.
c
Exact indications for drugs approved prior to 1985 are not well documented nor publicly available from the FDA.
Review
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Malignancy Therapeutics Non-Malignant
Figure 1. Repurposing therapeutics

Therapeutics utilized in malignancies have been applied or have potential to be applied in
nonmalignant conditions including but not limited to Alzheimer’s disease, inflammatory bowel
disease, COVID-19, sickle cell anemia, renal transplant, kidney transplant, multiple sclerosis,
neurodegenerative disorders, rheumatoid arthritis, precocious puberty, endometriosis, atopic
dermatitis, psoriasis, pulmonary fibrosis, CAR T cell-associated cytokine release syndrome,
seizures, dwarfism, and a variety of other congenital syndromes. Created in BioRender.com.
drug product labeling from the FDALabel online database (https://nctr-crs.fda.gov/

fdalabel/ui/search). Therapies that had nonmalignant FDA-approved indications in
addition to malignant indications were included (Tables 2, 3, and S1). The data
curated demonstrate that a wide variety of nonmalignant disorders, ranging from
congenital/hereditary conditions with and without predisposition to cancer to ac-
quired illnesses such as inflammatory and autoimmune conditions, are caused by al-
terations in pathways as well as identical alterations in specific genes that also drive
cancer and hence suggest the possibility that targeted drugs developed for cancer
may be more widely repurposed for treating nonmalignant illnesses (Figure 1).
DRUG REPURPOSING BASED ON GENE/PATHWAY ABERRATIONS

AND THERAPEUTIC CLASSES
Intriguingly, a significant number of molecular pathways are altered in both nonma-
lignant and malignant conditions, often with the exact same gene mutation being
responsible for both types of conditions. Moreover, several drugs or drug classes
now carry approvals for both benign and malignant conditions. Examples include
but are not limited to MEK and PI3K/AKT/mTOR pathway inhibitors, fibroblast
growth factor receptor (FGFR) and JAK2 inhibitors, Bruton’s tyrosine kinase inhibi-
tors, and CD20-directed antibodies (CD20 being a B cell surface marker). Im-
portantly, many nonmalignant but serious illnesses, including but not limited to
Alzheimer’s and other neurodegenerative diseases, endometriosis, dwarfism syn-
dromes such as achondroplasia, and autoimmune/inflammatory conditions, harbor
molecular pathway aberrations or even specific genomic mutations implicated in
cancer. Several examples are shown in Figures 2 and 3.
Targeting gene/pathway aberrations found in cancer and noncancerous

conditions
There are a number of both druggable and not yet druggable driver genes found
altered in malignancy that also have similar or indistinguishable alterations that char-
acterize benign, premalignant, hereditary germline conditions, and/or somatic
mosaic conditions.17,18 Why some of these nonmalignant conditions do not develop
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Ruxolitinib Atopic dermatitis
Multiple cancers
PROS syndromes Trametinib
P
JAK
P
JAK AVM
Alpelisib P
P RA
S
GT -
P
Breast cancer Multiple cancers

PI3K Ra
f
ERBB3/4
AKT Afatinib
P
ME
Multiple sclerosis K
P
mTOR NRG1 ALS
Ofatumumab
CD20
Lymphoma BTK
Bladder Cancer
PIP3
FGFR
Chronic GVHD
Ibrutinib CLL/SLL
Figure 2. Examples of druggable molecular targets with potential for or established reversed
repurposing from cancer to nonmalignant diseases
Repurposed therapeutics as examples: afatinib (EGFR/pan-ERBB inhibitor), alpelisib (PI3KCA
inhibitor), erdafitinib (FGFR1-4 inhibitor), ibrutinib (BTK inhibitor), ofatumumab (CD20-directed
antibody), ruxolitinib (JAK inhibitor), and trametinib (MEK inhibitor). Repurposed therapeutics that
are already approved for nonmalignant conditions are in green. Drugs in red reflect therapeutics
that have theoretical and/or clinical-based evidence for use in the nonmalignant condition but are
not approved for such use at this time. Created in BioRender.com. ALS, amyotrophic lateral
sclerosis; AVM, arteriovenous malformation; BTK, Bruton’s tyrosine kinase; CLL, chronic
lymphocytic leukemia; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor
receptor; GVHD, graft-versus-host disease; JAK, Janus kinase; MEK, mitogen-activated
extracellular kinase; PROS, PIK3CA-related overgrowth spectrum; SLL, small lymphocytic
lymphoma.
into malignancy is a fascinating question, which remains for the most part unan-
swered. Even so, targeted therapeutics used in oncology have potential to treat
these conditions. Table 1 provides examples of targeted therapeutics with FDA ap-
provals, clinical data, or with theoretical value for nonmalignant conditions with mu-
tations in oncogenic drivers.
BRAF/MEK pathway alterations and BRAF/MEK inhibitors

The RAF-MEK-ERK signaling cascade is a well-characterized pathway involved in cell
proliferation and survival. Alterations of this pathway are found in over one-third of
cancers and are considered strong drivers of oncogenesis.72 It is therefore rather un-
expected that identical gene anomalies are found in many different nonmalignant
conditions.
As an example, BRAF alterations occur in approximately 15% of cancers,73 and they

can be effectively targeted across most cancers with approved BRAF (e.g., vemura-
fenib, dabrafenib, and encorafenib) and/or MEK inhibitors (e.g., trametinib, cobime-
tinib, and binimetinib). Indeed, the combination of the BRAF inhibitor dabrafenib
and the MEK inhibitor trametinib has received a tissue-agnostic FDA approval for
solid cancers harboring BRAFV600E mutations.74 Paradoxically, activating, delete-
rious BRAF mutations (i.e., BRAFV600E) occur in 75% of benign melanocytic
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TP53 Tocilizumab
~40% of cancers in rheumatoid
arthritis
in
FGFR3
achondroplastic
~2.5% of cancers
TSC1/2 Everolimus
~2% and ~3.5% in TSC partial
of cancers seizures
Alpelisib in
PI3K pathway endometriosis
~38% of cancers (theoretical)
KRAS Trametinib
~16% of cancers in AVM
Everolimus in
PTEN hamartoma
~7% of cancers syndrome for
neurocognitive
Trametinib function
MEK pathway
in Noonan
~33% of cancers
syndrome
cardiomyopathy
Figure 3. Examples of identical gene alterations in malignant and nonmalignant diseases and potential for or established reversed drug repurposing
from malignant to benign disease
Therapeutics repurposed and/or developed to target specific sequelae of gene alterations shared by cancer and non-cancer conditions: alpelisib
(PI3KCA inhibitor), everolimus (mTOR inhibitor), infigratinib (FGFR1-3 inhibitor), tocilizumab (IL-6 inhibitor), and trametinib (MEK inhibitor). Therapies
already approved for nonmalignant indication in green. Drugs in red reflect therapeutics that have theoretical and/or clinical-based evidence for use in
the nonmalignant condition but are not approved for such use at this time. Created in BioRender.com. AVM, arteriovenous malformation; FGFR,
fibroblast growth factor receptor; IL-6, interleukin-6; JAK, Janus kinase; MEK, mitogen-activated extracellular kinase; mTOR, mammalian target of
rapamycin; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; TSC, tuberous sclerosis complex.
proliferations such as nevi despite the near complete lack of evolution of these
benign nevi into melanomas; moreover, BRAFV600E, a clearly targetable driver sus-
ceptible to FDA-approved BRAF or MEK inhibitors, occurs in only 50%–60% of mel-
anoma, hence less than in its benign counterpart.75,76 There are case reports of invo-
lution of benign nevi after MEK pathway therapy (e.g., with cobimetinib),77 though
this may not be a common occurrence. NRAS alterations and BRAF-activating alter-
ations including fusions have also been seen in giant congenital melanocytic nevi78
and may be treatable with MEK inhibitors.52,54
The RASopathies are a group of inherited syndromes that are caused by germline
pathogenic alterations in genes encoding the RAS/MEK signaling pathway.79 As
an example, Noonan syndrome is an autosomal dominant disorder characterized
by widely set eyes, low-set ears, short stature, and pulmonic stenosis; the gene
defect is usually in PTPN11 also known as SHP2. PTPN11/SHP2 mediates RAS/
MEK/ERK activation through Grb2-associated binder protein. Cardiofaciocutaneous
syndrome and Costello syndrome are other examples of RASopathies. For unknown
reasons, RASopathy-associated cancers are usually of different histological origin
than those seen with sporadic mutations of the same genes.80 The preclinical eval-
uation of targeted agents specific for the RAS/MAPK pathway in models of RASopa-
thies suggest that MEK inhibitors show therapeutic promise.28,29,79 Furthermore,
clinical successes have been reported. For instance, there are reports of reversal
of severe hypertrophic cardiomyopathy and chylous effusions in children with
Noonan syndrome treated with the MEK inhibitor trametinib.44–46
Somatic KRAS alterations have been reported in AVM of the brain (a leading cause of
hemorrhagic stroke in young people).42 Case reports demonstrating successful
treatment of AVM with the MEK inhibitor trametinib have been published,4,5 and
preclinical mouse models support trametinib as a therapeutic option.43
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There is theoretical benefit from MEK inhibitors for treatment of endometriosis. An-
glesio and colleagues found that lesions in deep infiltrating endometriosis, which is
associated with virtually no risk of malignant transformation, harbor somatic cancer
driver mutations, including in PIK3A and KRAS genes.81 The resultant intensification
of kinase signaling represents a viable target for repositioning cancer drugs that sup-
press the PI3K/AKT/mTOR or MEK axis in order to treat endometriosis.82
Alzheimer’s disease is a progressive neurodegenerative disorder and the most com-

mon cause of dementia worldwide, with no adequate treatment. The prevalence of
Alzheimer’s disease is increasing dramatically due to the aging of the world popula-
tion. Pathogenic brain somatic mutations identified in a subset of individuals
suffering from Alzheimer’s disease are enriched in PI3K-AKT and MEK pathway
gene aberrations known to contribute to hyperphosphorylation of tau, a micro-
tubule-associated protein that accumulates as neurofibrillary tangles in Alzheimer’s
disease.83 Hence there is growing interest in these pathways as therapeutic targets
for Alzheimer’s disease.
Neurofibromatosis type 1 (NF1) is a hereditary disorder characterized by NF1 alter-

ations, which activate the MEK pathway; selumetinib is an MEK inhibitor that is FDA-
approved for treatment of people with NF1 who have symptomatic, inoperable plex-
iform neurofibromas,84 and clinical data are also present for use of trametinib in this
disorder.48
ARAF recurrent mutations can cause central conducting lymphatic anomaly; in a

child, treatment with an MEK inhibitor resulted in remodeling of the patient’s
lymphatic system with resolution of the lymphatic edema as well as marked improve-
ment in his pulmonary function tests, with cessation of supplemental oxygen require-
ments and near normalization of daily activities.85
PI3K/AKT/mTOR pathway alterations and inhibitors

Genes in the PI3K/AKT/mTOR pathway are frequently aberrant in a wide range of
cancers, being discerned in almost two-fifths of malignant neoplasms.6 The pathway
can be targeted by multiple approved cancer drugs, including but not limited to al-
pelisib (PIK3CA inhibitor), capivasertib (AKT inhibitor), and nab-sirolimus, everoli-
mus, and temsirolimus (mTOR inhibitors).7 There are also diverse nonmalignant con-
ditions that harbor alterations in this pathway, with the potential for repositioning of
cancer drugs.
Several inherited or mosaic conditions are due to alterations in the PI3K/AKT/mTOR

pathway. As an example, tuberous sclerosis complex is an autosomal dominant dis-
order characterized by skin manifestations and formation of multiple tumors in
different organs, mainly in the central nervous system. Tuberous sclerosis is caused
by the mutation of one of two tumor suppressor genes, TSC1 or TSC2, which in turn
leads to activation of the mTOR pathway.86 It is fascinating that the FDA has
approved everolimus, an mTOR inhibitor authorized for cancer, for tuberous scle-
rosis complex-associated partial-onset seizures.87 PTEN is altered in hamartoma tu-
mor syndrome55 (includes Cowden’s disease), an autosomal dominant genoderma-
tosis in which noncancerous hamartomas develop in different body areas. In this
disorder, PTEN germline alterations generally result in PTEN loss of function that
secondarily upregulates the PI3K/AKT/mTOR axis. Intriguingly, again, there is
improvement including in neurocognitive symptoms following everolimus treat-
ment.56 These results indicate that matched molecular targeting can ameliorate
nonmalignant sequelae of gene defects, including neurologic impairment.
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Neurofibromatosis-2 is characterized by germline NF2 mutations, which in turn acti-

vate the PI3K/AKT/mTOR axis51; there are clinical data supporting the use of temsir-
olimus for this condition.49 Peutz-Jegher syndrome is a hereditary syndrome charac-
terized by gastrointestinal polyposis, mucocutaneous pigmented macules, and
predisposition to certain cancers. It is caused by germline STK11 mutations, which
activate the mTOR axis, potentially suggesting that mTOR suppression might be a
treatment option that merits study.58,88
Proteus syndrome is generally characterized by a mosaic AKT1 pathogenic variant

(not germline) with progressive patchy overgrowth of the skeleton, skin, adipose,
and central nervous systems, causing severe disfigurement, starting from the
toddler stage, and predisposition to deep vein thrombosis, pulmonary embolism,
and a range of tumors.89 There are clinical data for the benefit for the AKT inhibitor
miransertib for proteus syndrome.23 PI3K pathway alterations have also been
observed in activated PI3K delta syndrome (APDS) (autosomal dominant inheri-
tance) and PROS, a heterozygous mosaic (or rarely, constitutional) syndrome due
to an activating deleterious PIK3CA mutation.9,18,71 Alpelisib is approved for
PROS,90 and leniolisib (selective PI3Kd inhibitor) is approved for APDS,91 which
is caused by mutations in PIK3CD or PIK3R1 genes that encode the PI3Kdelta
protein.
PIK3CA alterations have also been observed in acquired benign conditions such as
seborrheic keratosis, endometriosis, and Alzheimer’s disease. Seborrheic keratosis,
though benign and without malignant potential, frequently displays the typical can-
cer-associated PIK3CA mutations E542K, E545K, and H1047R.92 SM-020 is a selec-
tive and potent AKT inhibitor applied by patients at home to their seborrheic kera-
toses lesions with preliminary positive results.93 In endometriosis, in addition to
alterations in the MEK pathway, as discussed above, alterations in the PI3K/AKT/
mTOR pathway are also common. A number of pharmaceutical compounds that
target these pathways have been successfully applied in preclinical models of endo-
metriosis.82 Finally, in Alzheimer’s disease, in addition to brain somatic mutations
identified in the MEK pathway, the PI3K-AKT pathway genes may also be mutated
and participate in Alzheimer’s pathogenesis, perhaps through hyperphosphoryla-
tion of tau.83
FGFR alterations and inhibitors

FGFRs are aberrantly activated through single-nucleotide variants, gene fusions,
and copy number amplifications in 5%–10% of human cancers.94 Several drugs
with FGFR inhibitory activity, including but not limited to erdafitinib, pemigatinib,
futibatinib, and infigratinib (recently withdrawn), achieved FDA approval for cancers
with cognate FGFR aberrations.94 In addition, other multikinase inhibitors such as
lenvatinib (FDA approved for several types of cancer, but approval not based on
an FGFR or other biomarker) have robust FGFR inhibitory activity. Importantly,
FGFR alterations also drive an assortment of inherited and acquired nonmalignant
illnesses.
Hereditary FGFR alterations have been observed in a variety of hereditary syn-

dromes, e.g., Hartsfield syndrome (autosomal dominant, FGFR1 loss-of-function al-
terations), Kallman syndrome (sometimes have loss-of-function FGFR1 alterations),
and Pfeiffer syndrome (gain-of-function FGFR1 or FGFR2 alterations, autosomal
dominant).95 Pfeiffer syndrome is now known to be a member of a group of condi-
tions caused by variants in the FGFR genes including Apert syndrome, Crouzon syn-
drome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, and
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Jackson-Weiss syndrome (all craniosynostosis syndromes with FGFR2 gain-of-func-

tion hereditary anomalies).96 Muenke syndrome is a craniosynostosis characterized
by FGFR3 gain-of-function mutations.97 FGFR inhibitors may theoretically be of
benefit in syndromes with gain-of-function FGFR alterations, but not in syndromes
with loss-of-function FGFR alterations.31
Of special interest, achondroplasia is the most common form of human dwarfism; it

is caused by germline activating FGFR3 mutations; significantly, though the FGFR3
mutations can be indistinguishable from those found as targetable somatic muta-
tions in some human malignancies such as bladder cancers, people with achondro-
plastic dwarfism do not have an increased incidence of cancer.98 Infigratinib, a
potent pan-FGFR inhibitor, is being investigated in children with achondroplastic
dwarfism, since FGFR inhibitors demonstrated the ability to reverse the achondro-
plastic phenotype in mouse models.32,33,99 In achondroplastic children, early re-
sults suggest that FGFR inhibitor therapy significantly increases height veloc-
ity.33,100 A question that will need to be answered is whether there is a change
in susceptibility to cancer in people who have pathogenic FGFR3 germline muta-
tions and pharmacological suppression from childhood, especially should they
stop the drug.
Neuregulins and ERBB family members and their inhibitors

Neuregulins are a family (NRG1 [types I–VI], NRG2, NRG3, and NRG4) of EGF-like
signaling molecules involved in the development and repair of diverse body ele-
ments including those of the nervous system, skeletal muscle, heart, breast, and
other organs. NRG1 has undergone significant study; it binds to ERBB3/HER3 and
ERBB4/HER4 and also influences EGFR/ERBB1/HER1 and ERBB2/HER2 receptor
signaling via heterodimerization with ERBB3/HER3 and ERBB4/HER4. NRG1-acti-
vating fusions can be found in diverse cancer types, albeit at a low rate: 0.15%–
0.5% across tumors.101 Of interest, there is growing evidence that elevated NRG1
expression may be implicated in the pathogenesis of amyotrophic lateral sclerosis
(ALS), Alzheimer’s disease, and schizophrenia. In ALS, it has been postulated that
NRG1 upregulation may occur in response to ERBB4 loss-of-function mutations,
which may in turn then overstimulate ERBB1, ERBB2, and ERBB3 signaling.30 It is
not known if drugs impacting NRG1 or its downstream effectors, such as the pan-
ERBB inhibitors afatinib, dacomitinib, or neratinib, which are approved for various
cancers, could impact the neurodegenerative and psychiatric diseases in which
NRG1 appears to be overexpressed.
Repurposing therapeutic classes

Multiple molecular targets are utilized for malignant and nonmalignant indications.
Inhibitors of Bruton’s tyrosine kinase (BTK), CD20, FGFR, phosphatidylinositol
3-kinase (PI3K), MEK, interleukin-6 (IL-6), mTOR, and Janus kinase (JAK), along
with gonadotropin-releasing hormone (GnRH) agonist/antagonist therapies are
summarized in Tables 2 and 3 and Figure 2.
The modes of action of these therapies in nonmalignant conditions are summarized

in Table 2. Autoimmune conditions can have abnormal B cell activation that is driven
by BTK and CD20 activation. T lymphocyte activation and proliferation leading to
rejection can occur through the mTOR pathway. Chronic inflammatory and autoim-
mune conditions may have IL-6 and JAK pathway activation. Abnormal cell prolifer-
ation can be driven by the PI3K, RAS, and FGFR pathways. Thus, specific inhibitors of
these pathways are approved and of benefit in a number of benign conditions.
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BTK inhibitors
There are four BTK inhibitors approved for malignant indications. Acalabrutinib,
ibrutinib, and zanubrutinib are all authorized for chronic lymphocytic leukemia
(CLL) and small lymphocytic lymphoma (SLL). Additionally, acalabrutinib is approved
for mantle cell lymphoma (MCL), ibrutinib for Waldenström macroglobulinemia, and
zanubrutinib for MCL, marginal zone lymphoma (MZL), and Waldenström macro-
globulinemia. Pirtobrutinib is approved for MCL. Ibrutinib also carries a nonmalig-
nant indication for chronic graft-versus-host disease (GVHD). BTK is hyperactivated
on B cells in chronic GVHD, and thus inhibition with ibrutinib can effectively treat this
nonmalignant disease.64,102
CD20-directed antibodies
Four CD20-directed antibodies are approved for malignant indications. Obinutuzu-
mab, ofatumumab, and rituximab are approved for CLL. Obinutuzumab is also
approved for follicular lymphoma (FL) and rituximab for non-Hodgkin’s lympho-
mas (NHLs). Ibritumomab tiuxetan is a CD20-directed radiotherapeutic antibody
approved in NHL.103
There are four CD20-directed antibodies approved for nonmalignant indications;

ocrelizumab, ofatumumab, and ublituximab are all approved for use in multiple scle-
rosis (MS), whereas rituximab carries indications for granulomatosis with polyangiitis
(GPA), microscopic polyangiitis, pemphigus vulgaris, and rheumatoid arthritis.
CD20-directed antibodies lead to the depletion of the pathogenic, self-reactive B
cells that drive these autoimmune diseases.65,104
FGFR inhibitors
The potential for targeting FGFR gain-of-function mutations that characterize
nonmalignant disease by repositioning FGFR inhibitors approved for cancer with
FGFR activating fusion/alterations/mutations has been discussed (see the section
FGFR alterations and inhibitors and Table 1). In addition to targeting FGFR muta-
tions, fibrosis may be causative for specific disorders, and FGFR inhibitors may
show activity in these conditions. For instance, nintedanib is an FGFR1-3 inhibitor
that is approved for several pulmonary indications including idiopathic pulmonary
fibrosis, progressive chronic fibrosing interstitial lung disease (ILD), and systemic
sclerosis-associated ILD.105 Nintedanib competitively inhibits multiple tyrosine ki-
nases, including FGFR1-3, blocking intracellular signaling cascades that are involved
in the pathogenesis of fibrotic tissue remodeling in ILD fibrosis, including fibroblast
proliferation, migration, and differentiation.106
PI3K pathway inhibitors

Four PI3K pathway inhibitors have been approved for oncology indications. Alpe-
lisib is approved for PIK3CA-mutated breast cancer. Copanlisib was approved for
use in FL; however, as of November 2023, it is being voluntarily withdrawn from
the market due to lack of efficacy seen in the confirmatory phase 3 trial. Duvelisib
and idelalisib are both approved for CLL. Alpelisib and a distinct PI3K-delta inhib-
itor, leniolisib, are approved for nonmalignant indications. Alpelisib inhibits the
PI3Ka pathway, preventing downstream overgrowths and malformations
comprising a wide group of clinically recognizable disorders commonly known as
PROS. Interestingly, alpelisib may also attenuate excessive insulin production in
congenital hyperinsulinemia through modulation of the PI3K pathway.107 Leniolisib
inhibits the PI3K delta pathway, preventing production of phosphatidylinositol
(3,4,5)-trisphosphate (PIP3), hyperactivity of the downstream mTOR/AKT pathway,
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and the proliferation and activation of B and T cell subsets seen in activated PI3K
delta syndrome (APDS).108–110
MEK inhibitors
There are three MEK inhibitors with oncology indications. Binimetinib and cobime-
tinib are approved for melanoma with BRAF V600E or V600K alterations. Binimetinib
is also approved for non-small cell lung cancer (NSCLC) with a BRAF V600E mutation
and cobimetinib for histiocytic neoplasms. There are multiple cancers with approvals
for trametinib in BRAF V600E or V600K mutated tumors and, more recently, trame-
tinib received a tissue-agnostic approval when given in combination with dabrafenib
for solid tumors with BRAF V600E mutations.111 Selumetinib is a distinct MEK inhib-
itor approved for neurofibromatosis type 1. Selumetinib inhibits MEK1/2, prevent-
ing downstream phosphorylation of ERK, leading to reduced neurofibroma
numbers, volume, and proliferation112,113 (see also the section on BRAF/MEK
pathway alterations and BRAF/MEK inhibitors).
IL-6 inhibitors
The IL-6 inhibitor siltuximab is approved for Castleman disease, a lymphoprolifera-
tive disorder whose hallmark is elevated IL-6 levels.63 Whether Castleman disease
should be considered an autoimmune disease or cancer is currently unclear, though
in patients with multicentric disease, the behavior can be similar to cancer.114 There
are three distinct IL-6 antibodies—satralizumab, sarilumab, and tocilizumab—that
have nonmalignant indications. Satralizumab is approved for neuromyelitis optica
spectrum disorder. Sarilumab is approved for polymyalgia rheumatica and rheuma-
toid arthritis. Tocilizumab is approved for chimeric antigen receptor (CAR) T cell-
associated cytokine release syndrome, COVID-19 treatment, giant cell arteritis,
rheumatoid arthritis, systemic juvenile idiopathic arthritis, and systemic sclerosis-
associated ILD. Satralizumab, sarilumab, and tocilizumab bind to both soluble and
membrane-bound IL-6 receptors, inhibiting IL-6-mediated signaling through these
receptors; IL-6 is involved in T cell activation, induction of immunoglobulin secre-
tion, initiation of hepatic acute phase protein synthesis, and stimulation of hemato-
poietic precursor cell proliferation and differentiation. IL-6 is also produced by syno-
vial and endothelial cells leading to local production of IL-6 in joints affected by
inflammatory processes such as rheumatoid arthritis.115
mTOR inhibitors
Several mTOR inhibitors are approved for oncology indications: everolimus is
approved for breast cancer, neuroendocrine tumors, renal cell carcinoma, and tu-
berous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma;
nab-sirolimus, for perivascular epithelioid cell tumor and temsirolimus is approved
for renal cell carcinoma116; and temsirolimus is approved for kidney cancer. Evero-
limus also has multiple nonmalignant indications: liver transplant, renal transplant,
TSC-associated partial-onset seizures, and TSC-associated renal angiomyolipoma.
Sirolimus, another mTOR inhibitor, is approved for facial angiofibroma associated
with TSC, kidney transplant, and lymphangioleiomyomatosis116 (see also the section
on PI3K/AKT/mTOR pathway alterations and inhibitors).
JAK inhibitors
There are four JAK inhibitors approved for oncology indications. Pacritinib, mome-
lotinib, ruxolitinib, and fedratinib are all approved for myelofibrosis. Ruxolitinib has
an additional approval for polycythemia vera. Somatic gain-of-function alterations in
various JAK genes are predominantly associated with hematologic malignancies.117
There are also multiple JAK inhibitors approved for nonmalignant indications.67 JAK
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pathway activation can lead to autoimmunity through T cell differentiation, lympho-

cyte effector function, and macrophage activation67; thus, JAK2 inhibitors can
benefit many autoimmune conditions. Abrocitinib is approved for atopic dermatitis.
Barictinib is approved for rheumatoid arthritis, alopecia areata, and COVID-19. Deu-
cravacitinib is approved for plaque psoriasis, ritlecitinib is approved for alopecia
areata, and ruxolitinib is approved for GVHD. The topical formulation of ruxolitinib
is also approved for atopic dermatitis and nonsegmental vitiligo. There are multiple
approvals for tofacitinib, which include rheumatoid arthritis, psoriatic arthritis, ulcer-
ative colitis, juvenile arthritis, and ankylosing spondylitis. Upadacitinib has approvals
for rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, Crohn’s disease, ulcer-
ative colitis, ankylosing spondylitis, and spondyloarthritis.67
Gonadotropin-releasing hormone agonists and antagonists

Gonadotropin-releasing hormone (GnRH) agonists and antagonists are short pep-
tide analogs of GnRH that suppress estrogen and androgen synthesis and are often
used as androgen deprivation therapy in patients with advanced prostate cancer.
Some of these agents are also administered to manage benign conditions respon-
sive to hormonal inhibition such as endometriosis, uterine fibroids, precocious pu-
berty, and infertility.118
Goserelin, histrelin, leuprolide, and triptorelin are GnRH agonists approved for pros-
tate cancer. Goserelin has an additional approval in breast cancer. Five GnRH ago-
nists also carry approvals in nonmalignant conditions. Goserelin, nafarelin, and leu-
prolide are each approved in endometriosis. Histrelin, leuprolide, and triptorelin are
each approved for central precocious puberty. Goserelin also has an approval for
endometrial thinning agent prior to endometrial ablation for dysfunctional uterine
bleeding, and leuprolide has an approval for uterine fibroids.
Degarelix and relugolix are GnRH antagonists approved for prostate cancer. Cetror-
elix and ganirelix are GnRH antagonists approved for controlled ovarian stimulation,
while elagolix is approved for endometriosis. Cetrorelix, elagolix, and ganirelix
competitively inhibit the GnRH receptors on the pituitary and induce rapid, revers-
ible suppression of gonadotropin secretion. Sustained dosing of elagolix leads to
a decrease in serum estradiol to postmenopausal levels, such that endometrial tissue
that depends on gonadal steroids for maintenance becomes quiescent. Short-term
dosing of cetrorelix or ganirelix delays the luteinizing hormone surge, and conse-
quently ovulation, in a dose-dependent fashion until ovarian stimulation with hCG.
Repurposed drugs
We found 36 therapeutics that have both FDA-approved malignant and nonmalig-
nant indications. These are summarized in Table 3. Original FDA indications are
listed in Table S1 (FDALabel [database online]: Drug Product Labeling. US Food &
Drug Administration. https://nctr-crs.fda.gov/fdalabel/ui/search). Examples of ther-
apies that are FDA approved for a malignant condition that have clinical data, but
are not FDA-approved, are summarized in Table S2.
Cytotoxic chemotherapy/nontargeted therapy

Cytotoxic chemotherapy blocks cell proliferation and growth in malignant condi-
tions and can lead to immunosuppression through prevention of immune cell prolif-
eration. Thus, many cytotoxic chemotherapeutics have shown benefit for nonmalig-
nant autoimmune conditions and those characterized by abnormal cell growth. A
pyrimidine nucleoside analog, 5-fluorouracil, was originally approved for colorectal
cancer prior to receiving additional approvals for breast cancer, gastric cancer,
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pancreatic cancer, and superficial basal cell carcinoma. It is also approved for actinic
keratosis. Cladribine is a purine nucleoside analog initially approved for hairy cell
leukemia and then later approved for MS. Methotrexate, a folate antimetabolite,
was originally approved for acute leukemia. It subsequently acquired approvals
for breast cancer, head and neck cancer, lung cancer, meningeal leukemia, mycosis
fungoides, non-Hodgkin’s lymphoma, osteosarcoma, and gestational trophoblastic
neoplasia. It is used for the autoimmune conditions of psoriasis, rheumatoid arthritis,
and polyarticular juvenile idiopathic arthritis. Mitomycin is an anticancer antibiotic
that was originally approved for gastric and pancreatic cancers. It is also used for ur-
othelial cancers and as an adjunct to glaucoma surgery. Mitoxantrone is an anthra-
cycline originally approved for acute myeloid leukemia. It is also approved for pros-
tate cancer and MS. Hydroxyurea is an antimetabolite that had an original malignant
approval in 1967. It is currently approved for chronic myelogenous leukemia and
head and neck cancer along with sickle cell anemia.
Targeted therapies
Alemtuzumab, a CD52-directed monoclonal antibody, was initially approved for B
cell CLL. It was later approved for MS. Daratumumab, a CD38-directed monoclonal
antibody, was originally approved for multiple myeloma and was later approved for
the nonmalignant condition light chain amyloidosis. Ofatumumab, a CD20-directed
monoclonal antibody was originally approved for CLL and was repurposed for MS.
Rituximab, a CD20-directed monoclonal antibody, was originally approved for
non-Hodgkin’s lymphoma. It was later approved for use in CLL. Nonmalignant indi-
cations include granulomatosis with polyangiitis, microscopic polyangiitis,
pemphigus vulgaris, and rheumatoid arthritis.
Alpelisib, a PI3K inhibitor, was originally approved for breast cancer, then later
received approval for PROS. Crizotinib is a multi-tyrosine kinase inhibitor originally
approved for NSCLC. It later received approvals for anaplastic large cell lymphoma
and the nonmalignant inflammatory myofibroblastic tumor. Everolimus is an mTOR
inhibitor initially approved for renal cell carcinoma. It has additional malignant indi-
cations of breast cancer, pancreatic neuroendocrine tumor, and subependymal gi-
ant cell astrocytoma associated with TSC. It is used for several nonmalignant indica-
tions that include liver transplant, renal angiomyolipoma with TSC, renal transplant,
and TSC-associated partial-onset seizures. Ibrutinib, a BTK inhibitor, was initially
approved for MCL and has subsequently received approvals for CLL/SLL and Wal-
denström macroglobulinemia. It is also approved for GVHD. Ruxolitinib, a Janus ki-
nase inhibitor, was initially approved for myelofibrosis then later polycythemia vera.
It has been repurposed to treat atopic dermatitis, nonsegmental vitiligo, and GVHD.
Interferon alfa-2b, an interferon, was originally approved for hairy cell leukemia. It
acquired additional approvals for FL, hairy cell leukemia, Kaposi sarcoma, and
melanoma. It is used in the treatment of nonmalignant conditions including condy-
lomata acuminata, hepatitis B, and hepatitis C. The monopegylated conjugate, ro-
peginterferon alfa-2b, was also later approved for polycythemia vera.
Hormonal agents
Leuprolide, a GnRH agonist, was originally approved for prostate cancer. It is also
approved for endometriosis, uterine fibroids, and central precocious puberty. Trip-
torelin, another GnRH agonist, was similarly first approved for prostate cancer with a
subsequent approval for central precocious puberty. Goserelin, a GnRH agonist,
was initially approved for prostate cancer prior to acquiring a breast cancer indica-
tion. It is also approved for endometrial thinning agent prior to endometrial ablation
for dysfunctional uterine bleeding, and endometriosis. Megestrol acetate is a
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progestin that was first approved for endometrial cancer. It acquired additional ap-
provals for breast cancer and for AIDS-associated anorexia/cachexia. Octreotide is a
somatostatin analog originally approved for carcinoid tumors and VIPomas. It is also
used for acromegaly.
Nonmalignant to malignant repositioning

There were nine therapies identified that were originally approved for a nonmalig-
nant indication and later received approval for a malignant indication (FDALabel
[database online]: Drug Product Labeling. US Food & Drug Administration.
https://nctr-crs.fda.gov/fdalabel/ui/search). All-trans retinoic acid is a retinoid
originally approved for acne vulgaris and then later approved for treatment of acute
promyelocytic leukemia. It is also approved for photoaging. Denosumab is a
RANKL-directed monoclonal antibody which was originally approved for osteopo-
rosis prior to approval for giant cell tumor of the bone. It is also approved to treat
hypercalcemia of malignancy and for prevention of skeletal-related events. Eflorni-
thine, an ornithine decarboxylase inhibitor, received its first approval for the infec-
tious disease indication of West African trypanosomiasis with central nervous system
(CNS) involvement, but was later also approved for hirsutism as a topical agent and
then for high-risk neuroblastoma. The GnRH agonist histrelin received its original
approval for central precocious puberty and was later approved for prostate cancer.
Imiquimod is a toll-like receptor 7 agonist that was originally approved to treat gen-
ital warts. It was later approved for basal cell carcinoma and is also used for actinic
keratosis. Lanreotide, a somatostatin analog, had its original approval for acro-
megaly. It was later approved for gastroenteropancreatic neuroendocrine tumors
and carcinoid syndrome. Raloxifene, a selective estrogen receptor modulator, was
originally approved for osteoporosis prevention. It was later approved for risk reduc-
tion for recurrence of invasive breast cancer. Sirolimus, an mTOR inhibitor, was
originally approved for kidney transplant. It was later approved for malignant peri-
vascular epithelioid cell tumor treatment. Additional nonmalignant indications
include facial angiofibroma associated with tuberous sclerosis and lymphangioleio-
myomatosis. Thalidomide was originally approved for erythema nodosum leprosum,
then later acquired approval for treatment of multiple myeloma.
Of note there were six therapies that were approved for use prior to 1960 for which it
was difficult to discern if the initial indication was malignant or nonmalignant. Five of
these therapies were corticosteroids. Prednisone, hydrocortisone, methylpredniso-
lone, and prednisolone all have approved indications in leukemia and lymphoma
treatment. They are all indicated in numerous conditions. The general classes of
approved indications include allergic states, collagen diseases, dermatologic dis-
eases, edematous states, endocrine disorders, gastrointestinal diseases, hemato-
logic disorders, ophthalmic diseases, respiratory diseases, and rheumatic disorders.
Dexamethasone is used for leukemia, lymphoma, and multiple myeloma. The
nonmalignant applications include allergic states, dermatologic diseases, endocrine
disorders, gastrointestinal diseases, and hematologic disorders. Fluoxymesterone
is a synthetic androgen approved for breast cancer, delayed puberty, and
hypogonadism.
CONCLUSIONS AND FUTURE DIRECTIONS

Drug repurposing is an important strategy to identify therapeutic agents from exist-
ing approved drugs or compounds in clinical trials and use them in a different dis-
ease. Since drug discovery is expensive and time-consuming, drug repurposing
can dramatically accelerate the timeline for application of successful therapeutics.
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In order to repurpose medications effectively, a deep knowledge of underlying

biology of various conditions and scientific bridging between specialties is critical.
Because cancer is one of the major causes of morbidity and mortality across the
globe, there has been an emphasis on drug repurposing for compounds developed
for benign illnesses that might be exploitable to treat cancer.119 Reverse repurpos-
ing of drugs from malignant disease to nonmalignant conditions has received less
attention and is hampered by limited cross-fertilization between fields.
Perhaps unexpectedly, there are numerous nonmalignant conditions that harbor

genomic alterations that, in the cancer field, are known to be druggable oncogenic
drivers. Although patients afflicted with some of the nonmalignant conditions char-
acterized by genomic aberrations indistinguishable from those found in cancer do
have a predisposition to cancer, others do not. It is puzzling as to why an oncogenic
driver can be present and cause disease, albeit without malignant transformation
potential. Regardless, it is now apparent that a variety of inherited and acquired
benign disorders share activation pathways with cancer, such as the MEK, PI3K/
AKT/mTOR, JAK, FGFR, and NRG/ERBB signals, and even the same molecular alter-
ations. Because some of these oncogenic drivers/pathways are targetable in cancer
patients with highly effective cognate agents, the question arises as to whether these
agents could be exploited to treat nonmalignant conditions sharing activation path-
ways and/or harboring identical mutations/alterations. To date, such repurposing of
drugs has proven effective for several conditions. For instance, the PIK3CA inhibitor
alpelisib (approved for breast cancer) is effective in reversing the phenotypic mani-
festations of PROS and may also ameliorate excessive insulin production in congen-
ital hyperinsulinemia through modulation of the PI3K pathway. MEK alterations such
as KRAS mutations (common in cancer) are found in AVMs, and MEK inhibitors such
as trametinib can anecdotally attenuate the impact of these AVMs. Everolimus, an
mTOR inhibitor, is approved for alleviating partial seizures that afflict patients with
tuberous sclerosis, a disease whose molecular hallmark is inherited TSC mutations
that upregulate the mTOR pathway. Everolimus can also improve neurocognitive
function in the PTEN hamartoma syndrome, a congenital syndrome due to germline
PTEN loss-of-function alterations that result in upregulation of the mTOR signal.
While there is great potential for repurposing oncology therapeutics to nonmalig-

nant conditions, there are several potential challenges to consider. Targeting molec-
ular alterations in the nonmalignant condition may have reduced efficacy compared
with the malignant condition. The threshold to administer a therapy with side effects
may be higher in nonmalignant conditions as compared with metastatic cancer. The
high cost of anti-neoplastic agents may be limiting in patients with nonmalignant
conditions who need to remain on continued therapy for years to decades. It is
also unclear whether ongoing therapy in nonmalignant conditions will predispose
to therapeutic resistance that will make these conditions harder to treat after initial
therapy.
Whether or not the use of targeted drugs that suppress the biologic impact of spe-
cific oncogenic mutations in conditions that have a cancer predisposition would also
decrease the likelihood of developing cancer is not known. Importantly, many
nonmalignant but serious illnesses, including but not limited to Alzheimer’s
disease and other neurodegenerative disorders, endometriosis, dwarfism syn-
dromes such as achondroplasia, and autoimmune/inflammatory conditions, harbor
pharmacologically tractable molecular pathway aberrations or even specific
genomic mutations implicated in cancer.
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SUPPLEMENTAL INFORMATION
Supplemental information can be found online at https://doi.org/10.1016/j.medj.
2024.04.008.
ACKNOWLEDGMENTS
R.K. is funded in part by National Institutes of Health grants 5U01CA180888-08 and
5UG1CA233198-05.
AUTHOR CONTRIBUTIONS
K.W., M.N., and R.K. wrote and reviewed the manuscript. S.K., S.B., and J.J.A. re-
viewed the manuscript.
DECLARATION OF INTERESTS
R.K. has received research funding from Boehringer Ingelheim, Debiopharm, Foun-
dation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medi-
mmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, and TopAlliance and
from the NCI as well as consultant and/or speaker fees and/or a position as an advi-
sory board member/consultant for Actuate Therapeutics; AstraZeneca; Bicara Ther-
apeutics, Inc.; Biological Dynamics; Caris; Datar Cancer Genetics; Daiichi; EISAI;
EOM Pharmaceuticals; Iylon; LabCorp; Merck; NeoGenomics; Neomed; Pfizer; Pre-
cirix; Prosperdtx; Regeneron; Roche; TD2/Volastra; Turning Point Therapeutics; and
X-Biotech. She also has an equity interest in CureMatch, Inc., and IDbyDNA; serves
on the board of CureMatch and CureMetrix; and is a cofounder of CureMatch. S.K.
serves as a consultant for Medpace, Foundation Medicine, NeoGenomics, and
CureMatch. He receives speaker fees from Chugai, Roche/Genentech, and Bayer
and serves on the advisory board for Pfizer. He has research funding from ACT Ge-
nomics, Sysmex, Konica Minolta, OmniSeq, Personalis, and Function Oncology.
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arteriovenous malformations (AVM), including those in the brain, a nonmalignant but

Other important examples of repurposing drugs relate to medications targeting

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Pfeiffer syndrome and would thus make futibatinib,

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premalignant Hereditary germline nonmalignant conditions frequency of pathway-targeted

while RET alterations in cancers

inhibitors rheumatica, rheumatoid arthritis inflammatory and autoimmune disease13

renal cell carcinoma, renal angiomyolipoma carcinoma (2009)

Malignancy Therapeutics Non-Malignant

Figure 1. Repurposing therapeutics

drug product labeling from the FDALabel online database (https://nctr-crs.fda.gov/

DRUG REPURPOSING BASED ON GENE/PATHWAY ABERRATIONS

Targeting gene/pathway aberrations found in cancer and noncancerous

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Ruxolitinib Atopic dermatitis

Breast cancer Multiple cancers

BRAF/MEK pathway alterations and BRAF/MEK inhibitors

As an example, BRAF alterations occur in approximately 15% of cancers,73 and they

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Alzheimer’s disease is a progressive neurodegenerative disorder and the most com-

Neurofibromatosis type 1 (NF1) is a hereditary disorder characterized by NF1 alter-

ARAF recurrent mutations can cause central conducting lymphatic anomaly; in a

PI3K/AKT/mTOR pathway alterations and inhibitors

Several inherited or mosaic conditions are due to alterations in the PI3K/AKT/mTOR

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Neurofibromatosis-2 is characterized by germline NF2 mutations, which in turn acti-

Proteus syndrome is generally characterized by a mosaic AKT1 pathogenic variant

FGFR alterations and inhibitors

Hereditary FGFR alterations have been observed in a variety of hereditary syn-

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Jackson-Weiss syndrome (all craniosynostosis syndromes with FGFR2 gain-of-func-

Of special interest, achondroplasia is the most common form of human dwarfism; it

Neuregulins and ERBB family members and their inhibitors

Repurposing therapeutic classes

The modes of action of these therapies in nonmalignant conditions are summarized

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There are four CD20-directed antibodies approved for nonmalignant indications;

PI3K pathway inhibitors

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pathway activation can lead to autoimmunity through T cell differentiation, lympho-

Gonadotropin-releasing hormone agonists and antagonists

Cytotoxic chemotherapy/nontargeted therapy

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Nonmalignant to malignant repositioning

CONCLUSIONS AND FUTURE DIRECTIONS

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In order to repurpose medications effectively, a deep knowledge of underlying

Perhaps unexpectedly, there are numerous nonmalignant conditions that harbor

While there is great potential for repurposing oncology therapeutics to nonmalig-

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