Received: 1 February 2023 Revised: 26 July 2023 Accepted: 27 July 2023

DOI: 10.1002/cso2.1051

REVIEW

Unraveling the dangerous duet between cancer cell

plasticity and drug resistance

Namrata Chatterjee1 Bhavana Pulipaka2 Ayalur Raghu Subbalakshmi3

Mohit Kumar Jolly3 Radhika Nair4,5

1 Department of Biotechnology and

Medical Engineering, NIT Rourkela, Abstract
Odisha, India Cancer cell plasticity is the ability of tumor cells to switch phenotypes and is
2 Department of Biology, Ashoka
one of the predominant requisites of cancer cells capable of undergoing metas-
University, Haryana, India
3 Centre
tasis. Cancer cell plasticity is also recognized as one of the major contributors to
for BioSystems Science and
Engineering, Indian Institute of Science, intratumoral heterogeneity, a critical factor underlying the progression of malig-
Bangalore, India nant tumors, which is known to modify tumor response and induce resistance
4 Rajiv
Gandhi Centre for Biotechnology, against various modes of therapy, thus posing a barrier to efficient cancer man-
Kerala, India
agement. Cancer cell plasticity is acquired by the subversion of cell signaling
5 Centre for Human Genetics, Bangalore,
India
pathways like mitogen-activated protein kinase pathway, phosphoinositide-3-
kinase, signal transducer and activator of transcription 3, Wnt, Hedgehog and
Correspondence Notch as well as cellular programs such as epithelial to mesenchymal transition
Radhika Nair, Centre for Human
Genetics, Bangalore 560100, India, India. and phenotypic plasticity. This complex phenomenon has been studied in many
Email: radhikanair@cgh.res.in cancer types like pancreatic cancer, colon cancer and breast cancer. This review
will explore the current understanding we have in breast cancer on the intrin-
sic molecular mechanisms of cancer cell plasticity and the resistance to various
types of cancer therapy that arise as a result of plasticity. We conclude by explor-
ing the potential novel therapies that specifically target the pathways leading to
plasticity and can be leveraged to treat patients living with the disease.

KEYWORDS
cancer cell plasticity, cancer stem cells (CSCs), epithelial to mesenchymal transition (EMT),
intratumoral heterogeneity, targeted therapy, therapy/drug resistance

1 INTRODUCTION metastasis and resistance to therapy has been recognized.

Cell plasticity is the phenomenon of specific genotypes
producing different phenotypes in response to changing
external cues. Plasticity has been widely studied as a
critical process involved in development and evolution,
but more recently its role in the progression of cancer,
(Figure 1, 2, Table 1)
Cancer cell plasticity and intratumoral heterogeneity
are particularly relevant in solid cancers like breast can-
cer and are intertwined with the concept of cancer stem
cells (CSCs). CSCs are a subset of cells in the tumor that
inherently have self-renewal and tumorigenic capacity.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the
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© 2023 The Authors. Computational and Systems Oncology published by Wiley Periodicals LLC.

Comput Syst Oncol. 2023;3:e1051. wileyonlinelibrary.com/journal/cso2 1 of 15

https://doi.org/10.1002/cso2.1051

2 of 15
In addition to driving cancer progression and metasta-
sis, CSCs also exhibit plasticity leading to drug resistance,
which contributes to the aggressive growth of a tumor.
Furthermore, the CSC paradigm and associated plasticity
have been proposed as a model to explain the phenomenon
of intratumoral heterogeneity, which refers to the phe-
notypic, genetic, and functional heterogeneity within the
cell population of a single tumor as well as between
primary and metastatic tumors that arise as a result of
intrinsic genetic programs and extracellular triggers. The
phenomenon of cancer cell plasticity [1, 2] allows the
cells to change their state thus giving rise to a heteroge-
nous cell population. Recent research has also found that
factors such as genetic mutations, external stimuli, or
signaling from the tumor microenvironment (TME) as
well as different environmental factors [3] can trigger the
transformation of already differentiated cells into CSCs,
indicating the presence of plasticity even at various stages
of differentiation in breast cancer [4].
The molecular mechanisms that are related to the
emergence of plasticity include the activation of intrinsic
mechanisms involved in signaling pathways like Notch,
mitogen-activated protein kinase pathway (MAPK),
Phosphoinositide-3-Kinase (PI3K), Wingless Related Inte-
gration Site (Wnt), Hedgehog (Hh) and Signal transducer
and activator of transcription 3 (STAT3) that work in
tandem to control tumor cell dynamics and cell-to-cell
communication. Cell-extrinsic factors like TME consisting
of the immune system as well as tumor cells and the
cancer-associated extracellular matrix (ECM) that contain
numerous receptors that have been strongly linked to
providing a niche for CSCs are also required for the
development of plasticity. We will not be focussing on
the role of the microenvironment in cancer cell plas-
ticity, which is an area of intense research [5, 6] with
some excellent review articles on this subject [7–9]. The
importance of cancer cell plasticity becomes even more
relevant in the context of therapeutic intervention in
the disease. Common treatments that exist for different
stages of cancer include surgery, hormonal therapy,
radiation therapy, chemotherapy, targeted therapy and
immunotherapy [10]. However, the major problem that
stands in the way of an effective treatment regime is
resistance to treatment. Therapy resistance poses a major
problem in effective cancer treatment with tumor cells
that are initially responsive, developing resistance later, or
having innate unresponsiveness to different anti-cancer
drugs. Resistance in any type of cancer generally stems
from both genetic and epigenetic factors like cell plasticity,
epithelial to mesenchymal transition (EMT), heterogene-
ity in cancer cells, or mutations in different genes [11,
12]. The need of the hour is to tackle the phenomenon of
therapy resistance in cancer cells by targeting the intrinsic
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CHATTERJEE et al.
pathways as well as extrinsic factors that facilitate cell
plasticity. Besides covering the mechanisms by which cell
plasticity contributes to resistance, we will also focus on
how we can target these pathways to negate therapeutic
resistance with an overarching aim to obliterate cancer
cells.
2 CELL-INTRINSIC PATHWAYS
INVOLVED IN CANCER CELL
PLASTICITY
Cancer cell plasticity is a consequence of the interplay of
genetic factors and programs, which lead to tumor progres-
sion and metastasis to distant organs and confers thera-
peutic resistance to breast cancer cells. Major intrinsic cell
signaling pathways like MAPK, PI3K/AKT/mammalian
target of rapamycin (mTOR), Wnt, STAT3, Notch, Hh and
transforming growth factor β (TGFβ) have been found
to be dysregulated in many cancer types and harbor the
potential to induce cellular plasticity in cancer cells [13].
The MAPK pathway or mitogen-activated protein kinase
pathway [14] represents a cascade of protein kinases that
are considered a key signaling pathway for the regula-
tion of cellular and molecular functions like proliferation,
apoptosis, differentiation and stress response [15]. The
emergence of the MAPK pathway stems back 30 years
ago [16] and is grouped into three families in mammals,
namely, extracellular signal regulated kinases (ERKs),
p38/SAKs, and c-Jun N-terminal kinases (JNKs) [17]. The
MAPK pathway in the canonical form gets activated by
a MAPK kinase kinase. In the case of the ERK pathway
of MAPK, rapidly accelerated fibrosarcoma (Raf) is the
Mitogen activated protein kinase kinase (MAPKK), which
activates MEK 1/2 and then mobilizes ERK 1/2. In JNK and
p38 pathways of the MAPK pathway, Transcription growth
factor β activated kinase 1 (TAK1), MEKs, Mixed Linage
Kinases (MLKs) and Apoptosis Signal Regulating Kinase
(ASK1) act as MAPKKs leading to the activation of MKK
4/7 and further downstream pathways involving Jun path-
way and MKK3/6, eventually leading to the activation of
p38 [18]. Genetic mutation of the MAPK pathway is seen
in 58% of all tumors with different frequencies of muta-
tions like 42.1% in the JNK pathway, 40.3% in p38, 33.7%
in ERK 1/2 pathway, and finally followed by only 6.1% in
ERK5 pathway [19].
There is evidence that aberrant activation of MAPK
pathways and their role in cancer cell plasticity may be
due to their role in the maintenance of CSCs. Loss of Dual
specificity phosphate-4 (DUSP4), a negative regulator of
the MAP kinase superfamily, leads to the development of
a CSC-like phenotype in basal breast cancer, which con-
fers plasticity to cells [20]. Singh et al. [21] focused on

CHATTERJEE et al.
MAPK pathway inhibitors against different DUSPs in rela-
tion to their contribution to plasticity and resistance and
found that the downregulation of DUSP1 specifically leads
to plasticity in melanoma cells. DUSPs are negative regula-
tors of the MAPK pathway and act in tandem to maintain
cell proliferation and survival. However in cancer, down-
regulation of the DUSP leads to aberrant expression of
the pathway, but the exact mechanism of downregulation
still remains unknown. It has also been reported that Six
Homeobox (SIX1), which is a developmental homeopro-
tein that activates the MAPK/ERK pathway, leads to the
development of CSC phenotype in luminal B breast cancer
type [22]. It was observed that overexpression of SIX1 in the
MCF7 cell line leads to an increase in tumor-initiating cells
through phosphorylation of ERK of the MAPK pathway.
Atypical MAPK pathway activation could also contribute
to promoting EMT leading to cancer cell plasticity [23,
24]. ERK3 overexpression is associated with an increase
in cell migration and morphological changes in breast
cancer cells [25]. Mutations in the BRAF gene lead to alter-
ations in the RAS(Rat Sarcoma)-RAF(Rapidly activated
fibrosarcoma)-MEK-ERK pathway [13], which has a major
role in developing drug resistance. The pivotal transcrip-
tional factor, Forkhead box C1 (FOXC1) mediates cancer
cell plasticity and metastasis via partial EMT, which in turn
leads to drug resistance. The expression of FOXC1 is medi-
ated by the p38 MAPK pathway. FOXC1 is a pro-metastatic
gene, which aids cellular plasticity in cancer cells through
transcriptional activation of genes like MMP10, SOX4 and
SOX13. MAPK mediates FOXC1 expression by regulating its
stability by binding and phosphorylation of p38 to Ser241
and Ser272 sites of FOXC1 [26]. It has also been observed
in the majority of cutaneous melanomas that mutations in
the MAPK pathway along with BRAF are the major driv-
ing factor for the development of cell plasticity [27]. BRAF
gene transcription is regulated by the MAPKKs of the
MAPK pathway. Thus, when the BRAF gene is mutated,
it is expressed by the MAPK pathway in its mutated form,
leading to aberrant expression of the pathway.
The MAPK pathway plays a pivotal role in cellular pro-
liferation in tumors like melanomas [28]. In oral squamous
cell carcinoma (OSCC) [29], the MAPK pathway is an inter-
mediary between the epithelial factor Grainyhead Like
Transcription Factor 2 (GRHL2) and the EMT-inducing
signal TGFβ [30]. In the OSCC cell line SCC9, inhibition
of MAPK signaling activated TGFβ signaling, which in
turn promotes the process of EMT. In the triple-negative
breast cancer (TNBC) subtype, MAPK signaling leads to
the enrichment of breast CSCs [31]. In SUM-159 and MDA-
MB-231 cells, depletion of pluripotency factors SRY-box
Transcription factor 2 (SOX2), Krϋppel-like factor 4 (KLF4)
and NANOG was seen upon the inhibition of the p38-
MAPK signaling pathway indicating its role in the induc-
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3 of 15
tion of breast CSC phenotype. In breast ductal carcinoma,
the MAPK-ERK pathway was involved in the cytoskeletal
reorganization and transition to a mesenchymal pheno-
type [32] via Rap1Gap (a GTPase-activating protein [33])
suppression, which increased the levels of MAPK/ERK.
MCF10ADCIS cells, which are a model of breast ductal car-
cinoma, show higher levels of Rap1Gap when compared to
the invasive MCF10ACa1D cells, which represent invasive
ductal cancer. Rap1Gap silencing in MCF10ADCIS cells
resulted in elevated levels of ERK/MAPK, which promoted
their invasive capabilities accompanied by skeletal struc-
ture re-organization and gain of mesenchymal capabilities
further consolidating the role of the pathway in cancer cell
plasticity. MAPK pathway can thus be considered as one
of the major pathways that orchestrate plasticity in can-
cer cells and could be an attractive target for therapeutic
intervention.
The second pathway that has a major role in can-
cer cell plasticity is the PI3K/AKT/mTOR pathway. The
PI3K/AKT/mTOR pathway [34] also known as the phos-
phatidylinositol 3 kinase/protein kinase B pathway, is
a highly conserved pathway affecting cellular processes
such as proliferation, survival, growth, metabolism, and
immune response [35]. The signaling pathway came
into prominence in 1977 with the discovery linking PI
kinase activity with viral oncogene-encoded Tyrosine
(Tyr)-kinase [36]. It also has an important role in various
oncogenic regulations and thus therapeutic targeting of
the PI3K pathway has been a key research area in cancer
biology.
In physiological conditions, activation of the
PI3K/AKT/mTOR pathway happens by either recep-
tor tyrosine kinases or G protein-coupled receptors [37].
Various factors like the cancer-testis antigen A-kinase
anchor protein 3 (AKAP3) [38] are known to aberrantly
activate the pathway leading to the development of cancer.
Zhan et al. observed that AKAP3 was upregulated in
cancerous cells of the breast leading to activation of the
PI3K/AKT/mTOR pathway to facilitate cell migration,
progression, and migration in breast cancer cells [39].
AKAP3 is an inhibitor of PTEN, which hinders the pro-
gression of cancer cells by binding and inhibiting PI3K.
Thus, in cancer cells, upregulation of AKAP3 leads to
Phosphatase and Tensin Homology (PTEN) inhibition
and activation of the PI3K pathway leading to cancer cell
growth and proliferation. This pathway mediates cellular
plasticity, which results in different cellular populations
within the tumor. It has been documented in several
studies that the pathway leads to the repression of the
tight junction proteins, which mediates cell plasticity.
Resistance of TNBC cells toward chemotherapeutic drugs
has been observed due to mutation in the PI3K3CA path-
way that encodes a subunit of PI3K leading to inhibition

4 of 15
of cell apoptosis and increased cell proliferation [40]. The
mutation in the PI3K3CA gene leads to the upregulation
of different proteins of the pathway like p110α, Akt and
mTOR and the downregulation of inhibitory protein
PTEN resulting in cell apoptosis inhibition and chemore-
sistance in the TNBC cell line MDA-MB-231. Another
study by Ghebeh et al., which focused on Fascin-mediated
chemoresistance in breast cancer, demonstrated that the
PI3K/AKT pathway mediates resistance [41]. The group
used xenograft tumor models to evaluate the effect of
Fascin in mediating chemoresistance in breast cancer
cells. The patient data analysis showed a direct correla-
tion of survival rate of patients who were treated with
chemotherapy and Fascin expression. The increase in
chemoresistance of the cancer cells was also attributed to
the PI3K pathway in parallel to increased Focal Adhesion
Kinase (FAK) phosphorylation, expression of X-linked
inhibitor of apoptosis protein (XIAP) and Livin, which
are inhibitors of apoptosis proteins and also proapop-
totic markers (Caspase 9, Caspase3, Poly (ADP-ribose)
polymerase 1(PARP)) suppression.
The PI3K pathway can induce EMT directly or through
its cooperation with other signaling pathways [42, 43].
Mitochondrial ribosomal protein L13 (MRPL13) was found
to be a pro-EMT factor as its depletion resulted in a
decrease in mesenchymal markers like Snail Family Tran-
scriptional Repressor 1 (SNAI1) and Vimentin (VIM) and
an increase in the levels of E-Cadherin (ECAD). Fur-
ther, it was observed that MRPL13 mediated EMT through
PI3K/AKT/mTOR signaling pathway. Interestingly the
PI3K/AKT pathway was involved in conferring resistance
to tamoxifen in addition to their role as promoters of EMT
in T47D cells [44] when Connexin43, an EMT inhibitor,
was silenced leading to a reduction in the levels of ECAD
as well as an increase of NCAD levels. The addition of
LY294002, a PI3K/Akt specific signaling inhibitor [45],
suppressed EMT, and FAK/PI3K/Akt upregulation con-
ferred the cells with resistance to cisplatin in addition
to promoting EMT [46], thus corroborating the role of
PI3K signaling in EMT progression. In this study, when
MDA-M-231 and MCF-7 cells were treated with LY294002,
mesenchymal factors like SNAI1, SNAI2, VIM and N-
Cadherin (NCAD) significantly decreased along with a
concomitant increase in the level of ECAD and made
cells sensitive to cisplatin treatment. Analysis using T47D,
MDA-MB-231 cell lines demonstrated that EMT induc-
tion by inorganic pyrophosphatase 1 was mediated by
the PI3K/AKT signaling pathway [47]. When the relation-
ship between Ki-Ras2 Kirsten rat sarcoma viral oncology
homolog (KRAS), PI3K/AKT and EMT was analyzed in
T47D cells, it was seen that KRAS depletion resulted in
the silencing of the signaling factors of PI3K/AKT, along-
side EMT inhibition as indicated by the reduced NCAD
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CHATTERJEE et al.
levels and VIM with increased levels of ECAD [48]. Thus,
all these studies demonstrate the pivotal role PI3K plays in
conferring plasticity to the cancer cells by dysregulation of
various factors of the pathway.
STAT3 is another important intrinsic cellular signaling
pathway in cancer cells. The signal transducers and acti-
vation of transcription (STAT) 3 is a part of the STAT tran-
scription factor family, which has seven highly conserved
and structurally similar members. Since its discovery in
1994, STAT3 has been linked with cell growth, apoptosis
and disorders including cancer [49]. The STAT3 signaling
pathway is activated by growth factors and cytokines lead-
ing to phosphorylation of STAT3. This causes homodimer-
ization and translocation to the nucleus where the complex
binds to DNA response elements and regulation of gene
transcription [50]. STAT3 is one of the main intrinsic sig-
naling pathways that gets aberrantly expressed in cancer
resulting in cancer cell inflammation. Different studies
have also linked the pathway with cancer cell plasticity
[51, 52]. Another cancer type where STAT3 hyperactiva-
tion leads to enhanced cancer cell proliferation, tumor
angiogenesis, invasion, and metastasis in colorectal cancer
[53]. STAT3 mediates key transcription factors responsi-
ble for inducing cellular plasticity and is hyper-activated
in colorectal cancer cells. In Estrogen Receptor-positive
(ER+) breast cancer cells, the STAT3/progesterone recep-
tor (PR) pathway mediates cell plasticity by inducing
Aurora-A kinase (AURKA) protein. In a study by Antonino
et al., AURKA activation was mediated by phosphorylation
of serine727-STAT3/serine294-PR transcriptional complex.
This led to the regulation of a stemness reprogramming
gene KLF4 by the transcriptional complex, thus promoting
plasticity and therapy resistance in the cells [52].
The involvement of the Wnt pathway in cancer plas-
ticity in its canonical form is well-established. However,
more recent research has uncovered the effect of the
aberrant functioning of the pathway through genetic and
epigenetic mechanisms in the initiation, progression, and
development of drug-resistant characteristics in various
cancers, which includes the modulation of cancer cell
plasticity. The role of the Wnt pathway in cancer was dis-
covered when mammary tumors were observed in mice
after infection with the murine mammary tumor virus
(MMTV) leading to the activation of the murine Int-1 gene,
which was later named Wnt-1. Later studies found that
the cytosolic concentrations of β-catenin, a homolog of
the Drosophila Armadillo protein with significant roles as
the regulator of intracellular adhesion and as a transcrip-
tional activator controlled by the signaling pathway, was
downregulated by a tumor-suppressor called adenomatous
polyposis coli (APC), while the Wnt1 protein upregulated
it, providing a basis for the Wnt β-catenin pathway-cancer
connection. The aberrant functioning of the pathway can

CHATTERJEE et al.
be observed in different cancers like colorectal, gastric,
and breast cancers with studies on genetically engineered
mouse models revealing that the induction of mammary
tumorigenesis occurs as a consequence of the dysregula-
tion of the Wnt/β-catenin pathway via the overexpression
of its activators such as Wnt and the targeted disrup-
tion or silencing of its inhibitors such as APC [54]. In
most cancers (most notably colorectal and gastrointestinal
cancers), mutations that result in loss-of-function in the
genes coding for the proteins involved in the Wnt path-
way that are responsible for the degradation of β-catenin
such as APC and Axin have been recognized. As a result,
the downregulation of the amount of free cytoplasmic β-
catenin is inhibited, resulting in the transcription of Wnt
target genes. A critical role of the Wnt pathway is also
observed in the maintenance of cancer cell plasticity. Dif-
ferent transcription factors like Snal1(Snail1), Snal2 (Slug),
TWIST1, ZEB1, and ZEB2 are the driving factors for the
transition between the epithelial and mesenchymal cells
through the signaling pathways like Wnt, Hh, Notch [55].
Genetic alterations in APC and RNF43 result in the upreg-
ulation of Snail, thus leading to a transition between the
two phenotypes [56]. Inhibition of GSK3β by the Wnt lig-
ands leads to an increase in stability of the transcription
factor Snail, thus leading to plasticity in the cancer cells
[57]. Li et al. linked the plasticity of the prostate CSCs
with a circadian rhythm gene PER3. Low levels of the gene
lead to activation of the Wnt pathway through phospho-
rylation of β-catenin pathway [58]. Upregulation of the
Wnt pathway is mediated by inhibitors of other differ-
ent pathways as well. For example, MEK inhibitors are
considered to activate the pathway through AIX1, which
is the point of interjection between the Ras-MAPK and
Wnt pathway. These inhibitors are associated with rapid
reduction of the AXIN1 protein, which in turn dissoci-
ates from GSKβ, thus activating the pathway [59]. Under
physiological conditions, the Hh pathway plays a vital role
in embryonic development by patterning the developing
neural tube, axial skeleton, limbs, skin, lungs, hair and
teeth. The first clue connecting the Hh signaling pathway
to cancer came as a result of the discovery that a mutation
in the tumor suppressor gene that encodes for a receptor
molecule found within the pathway called patched was
an underlying factor in the development of both famil-
ial and sporadic forms of basal cell carcinoma. The Hh
pathway is involved in EMT transition in different types
of cancer cells [8]. A study by Zhu et al. found that CSC-
regulated expression of tetraspanin 8 (TSPAN8) leads to
activation of the Sonic-Hh pathway. The cascade of reac-
tions that follow the interaction of TSPAN8 with PTCH1
in turn inhibits degradation of the SH/PTCH1 complex
[60] resulting in CSC-like phenotypes and resistance to
chemotherapy. A study by Cazet et al. linked the Hh path-
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5 of 15
way as a key modulator for the plasticity of the CSCs
in TNBC. Hh pathway acts by the reprogramming of the
cancer-associated fibroblasts to a CSC supporting pheno-
type by activation of the fibroblast growth factor 5 and
fibrillary collagen secretion [61]. The Notch pathway is a
tightly controlled signaling pathway responsible for vari-
ous aspects of development in metazoans as well as the
renewal of tissue. As a conserved signaling pathway, it
plays a critical role in short-range communication between
cells by establishing physical contact between the target
cells. The pathway is responsible for enabling or suppress-
ing, depending on context and molecular cues, cellular
functions like cell differentiation, proliferation, cell death
and controlling cell fates throughout the development of
the organism as well as in self-renewing adult tissue. Given
the vital role it plays, the misregulated loss- or gain-of-
function of the Notch pathway can give rise to various
human diseases including cancer. Dysregulation of Notch
has also been linked to the maintenance of CSCs. In breast
cancer specifically, studies have shown that Notch acts as
an oncogene. The overexpression of the Notch proteins 1, 3,
or 4 has been shown to transform normal breast epithelial
cells into cancer cells. An ECM glycoprotein, tenascin-C
(TNC) is observed to promote cancer cell plasticity via acti-
vation of the Notch pathway in glioblastoma multiforme.
It was observed using PCR (Polymerase Chain Reaction)
and microarray technology that TNC elevates the signal-
ing components of the pathway—JAG1, ADAMTS15 and
NICD 1/2 [62, 63]. Notch pathway is also observed to pro-
mote CSCs in colon cancer leading to cellular plasticity and
chemoresistance [64]. The cascade of events involves the
induction of another receptor of the pathway—Jagged 1,
which in turn activates CD44, Slug, and SMAD expression,
progressing to an EMT phenotype in the cancer cells [65].
In another study by Ishida et al., a hypoxic environment
is an inducer of EMT via activation of Notch signaling
pathway; however, the exact mechanism of how they are
linked is still unknown [66].We tried to summarize the role
of different pathways in mediating the cellular plasticity
in tumors and the potential role as therapeutic targets in
curbing the same. However, more in-depth knowledge has
to be developed to completely understand the role of differ-
ent pathways and their link with plasticity in cancer cells.
(Figure 1)
3 DRUG RESISTANCE MEDIATED BY
CANCER CELL PLASTICITY
While chemotherapy is the mainstay in our battle against
cancer, intrinsic or extrinsic factors can unfortunately lead
to cancer cells acquiring the ability to evade the effect
of drugs [67]. One factor for the development of drug
 26899655, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cso2.1051 by Nat Prov Indonesia, Wiley Online Library on [19/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 of 15 CHATTERJEE et al.

F I G U R E 1 Cell intrinsic pathways involved in cancer cell plasticity. The major cellular signaling pathways involving multiple pathways
like MAPK, PI3K-AKT-mTOR, STAT3, Wnt, Notch and Hedgehog are key players in promoting cellular plasticity and therapy resistance in
cancerous cells. Targeted therapeutic approach toward these pathways can lead to avenues leading to curing this deadly phenomenon. JNK:
c-Jun N-terminal kinases, MAPK: mitogen activated protein kinases, Raf: rapidly accelerated fibrosacroma, MEK 1: Mitogen-activated protein
kinase kinase, ERK: extracellular signal regulated kinase, STAT3: signal transducer and activator of transcription 3, PI3K:
phosphoinositide-3-kinase, AkT: Ak strain transforming, mTOR: mammalian target of rapamycin, NCID: Notch intracellular domain, MAM:
mitochondria-associated ER membrane, GLI1/2: human glioma associated oncogene homolog 1/2, TCF/LEF: T-cell factor/lymphoid
enhancer factor.

resistance is plasticity. Different pathways as discussed
above have been shown to be involved in the phenomenon
of cancer cell plasticity leading to resistance toward drugs.
A recent study has linked the translocation of CD24 to phe-
notypic switching through cellular plasticity induction via
the p38 MAPK pathway. In breast cancer, CD44 and CD24
are the predominant CSC markers to identify the cells
at different stages of differentiation. CD44−/low CD24+ cell
population is predominant in luminal breast cancer, and
CD44+ CD24−/low in basal and mesenchymal breast cancer
[68–70]. Many studies have linked the presence of different
breast CSCs (BCSCs) markers to the development of cellu-
lar plasticity in cancer cells. CD44+ CD24− is observed to
have a correlation with increased metastatic and plastic-
ity potential [71]. A study by Hugh et al. focused on the
localization pattern of CD24 indicating the development
of plasticity [72]. The cellular localization of CD24 is medi-
ated by p38 MAPK pathway activation with phosphoryla-
tion leading to Bcl-2 overexpression in the cell membrane
[73] and treatment resistance. Non-genomic factors like
estrogen mediate cellular plasticity in the tumor cells that
have a propensity toward undergoing EMT. Estrogen bind-
ing leads to the activation of c-Src, which in turn mediates
cell signaling pathways like MAPK [74]. Thus, estrogen has
an indirect connection with the activation of the MAPK
pathway. Targeting these factors can yield a therapeu-
tic intervention point to check the treatment resistance
mediated by cellular plasticity. Radiotherapy is the use of
radiation to curb the growth and proliferation of cancer
cells. The effectiveness of radiotherapy is compromised
by adaptive radioresistance or the acquisition of resis-
tance by the cells over a period of time. In radioresistant
breast cancer cell lines, a major factor for acquired resis-
tance is an increase in CSCs alongside elevated Epithelial
Cell-Adhesion Moelcule (EpCAM) expression. Elevated
EpCAM expression conferred resistance toward radiother-
apy in breast cancer cell line ZR-75-1 by enhancing Akt
expression, which in turn increases the stemness of the
cells and induces cellular plasticity through inducing EMT
phenotype in the cancer cells. Thus, this pathway act as a
driving factor for EpCAM-mediated cellular plasticity [75].
A study by Arnold et al. found radiation to be respon-
sible for conferring radiation-mediated cellular plasticity
in breast cancer stem-like cells resulting in radioresis-
tance [76]. The findings of these researchers confirmed
that resistance and changes in cellular plasticity in the
TNBC cell line were mediated by STAT3 via an inflam-
matory response. The inflammatory response is mediated

CHATTERJEE et al.
by Interleukin-6 (IL6) leading to the activation of the
Janus family kinase and the STAT3 pathway. Resistance
toward the drug lapatinib in locally advanced Human
Epidermal Growth factor Receptor-2 positive (HER2+)
breast cancer is mainly mediated by Interleukin-8 (IL-8)
that is secreted from tumor macrophages via activation
of Src/STAT3/ERK1/2 pathway [77] and confers radio-
resistance to breast cancer cell lines. Activation of the
STAT3 pathway occurs by phosphorylation of Tyr705
residue of the signal transducer [78] and underscores the
importance of targeting STAT3 in breast cancer.
Hyperactivated Wnt pathway and the resultant dysreg-
ulation of the proteolytic degradation of β-catenin is also
strongly linked to the development of drug resistance
in many invasive cancers [79]. Conventional chemother-
apy affects cancer cells by exposing them to cytotoxic
agents that inhibit cell proliferation and induce cell death
in rapidly proliferating cells, while radiotherapy involves
the utilization of ionizing radiation, damaging their DNA
and resulting in cell death. CSCs are generally known
to be more resistant to chemo and radiation therapies as
compared to the non-stem cell populations in the tumor,
causing a relapse even after treatment [80]. Given that the
Wnt signaling pathway plays an important role in main-
taining CSCs, it could be a major mechanism underlying
the development of therapeutic resistance. A study using
carboplatin-resistant in vivo patient-derived xenografts as
well as isogenic TNBC cell-line models found that there
was an increased activation of the Wnt/β-catenin path-
way, which was correlated with the expression of stem
cell markers in the models studied. Moreover, they also
demonstrated that the inhibition of the Wnt signaling
pathway in these models resulted in their resensitization to
carboplatin from their resistant states—thus highlighting
a potential mechanism for overcoming chemotherapeutic
resistance, especially in breast cancer [81]. More evidence
comes from studies where ST8SIA1 and its correspond-
ing mRNA were upregulated in chemotherapy-resistant
TNBC patients. Inhibition of ST8SIA1 led to increased
efficacy of chemotherapy through the suppression of the
Wnt/β-catenin pathway [82].
Studies have also revealed the role of plasticity-mediated
drug resistance in cancer cells [83] via the Hh pathway
through the upregulation of different proteins like OCT4,
BMI 1 and SOX 2, which increased stemness and drug resis-
tance [84]. In studies by Magistri et al. and Nguyen et al.,
it was observed that Smoothened (SMO) inhibition leads
to the overexpression of two Hh target genes, GL1 and
GL2, which are the transcription factors responsible for
the upregulation of the master gene Snail that is known
for promoting plasticity in the cancer cells [85]. Targeting
these factors of the pathway could lead to a reduction in
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7 of 15
the plasticity of cancer cells and provide newer therapeutic
avenues.
One of the initial theories to explain the phenomenon of
drug resistance in breast cancer involves BCSCs, which are
thought to be inherently resistant to cytotoxic and targeted
therapies. Recent research has found evidence that links
Notch1 and Notch4 in the development of drug-resistant
behavior exhibited by BCSCs. A study using polyoma
middle T (MMTV-PyMT) mammary tumor mouse model
also showed that cells showed a temporal increase in
expression of the Notch ligand, DII1, as the tumor pro-
gressed from early to late stages. Moreover, these DII1+
cells also exhibit chemotherapeutic-resistant gene signa-
tures, and the consequent blocking of the ligand sensitized
the cells to chemotherapy as well as inhibiting tumor
growth and metastasis [86]. The Dll1+ cells were enriched
with genes that aid the process of plasticity and are thus
associated with increased cellular plasticity. Moreover, the
small interfering RNA- mediated knockdown of Notch1 in
ALDH+ cells, resulted in an inhibition of their growth and
increased apoptosis and tumor growth in mice models [87].
Jagged-1 receptor of the Notch pathway is overexpressed
through SLUG upregulation and in turn, represses E-
cadherin thus allowing EMT and resistance in the cancer
cells [88].
4 POTENTIAL TREATMENTS
TARGETING CELL-INTRINSIC
PATHWAYS MEDIATING CANCER CELL
PLASTICITY
The molecular mechanisms in cancer cell plasticity that
contribute to resistance remain to be elucidated com-
pletely. Research has paved the way for targeting various
crucial factors that play a role in conferring cellular
plasticity and therapy resistance in breast cancer cells.
These factors can thus act as potential biomarkers for tar-
geted therapy and for the development of new treatment
modalities.
One of the proteins in the MAPK pathway that is linked
to plasticity and resistance is the MEK protein. Drugs tar-
geting the MEK protein have been observed to lead to
improvement in the prognosis of breast cancer patients.
One such targeted therapy involved a combinational ther-
apy of RAF/MEK inhibitor CH5126766 with eribulin in
TNBC that successfully in inhibiting apoptosis and cell
migration, thus contributing to tumor growth [89]. In
another study, dual inhibition of MEK1/2 and MEK 5 using
inhibitors cobimetinib and trametinib resulted in the sup-
pression of EMT in TNBC [90]. Mohan et al. have also
shown that brucein D, which is an inhibitor targeting the

8 of 15
p38 pathway leads to apoptosis and decreases the viability
of breast cancer cells by inhibiting the MAPK pathway [91].
PI3K/AKT/mTOR pathway is another altered pathway
in breast cancer cell plasticity. Inhibition of the pathway
using small molecule inhibitors targeting different compo-
nents of the pathway has emerged as an area of research
interest. In vitro studies using inhibitors like buparlisib,
pictilisib, alpelisib, and taselisib have demonstrated pro-
apoptotic and anti-proliferative activity on breast cancer
cell lines [92]. Natural compounds have also started to
gain popularity for potential targeting of the pathway. One
such bibenzyl compound is gigantol extracted from orchids
belonging to the Dendrobium genus. It has been observed
to downregulate the PI3K/Akt/mTOR pathway in cancer
cells thus in turn inhibiting proliferation and inducing
apoptosis. The study involved in silico determination of
the potential pathway by which gigantol acts followed by
in vitro assays to elucidate their effect on breast cancer cell
lines [93]. Possible target identification for gigantol identi-
fied PI3K, mTOR, and Akt as potential targets. Molecular
docking studies provided the exact binding sites of the
drug, which were then validated using in vitro methods.
Another natural compound that has emerged as a potential
candidate for therapy in TNBC is a novel anilide shikonin
ester, M9. Studies on the breast cancer cell line MDA-MB-
231 showed that M9 has the ability to induce apoptosis and
arrest the cell cycle by affecting both the PI3K/Akt/mTOR
and Wnt/β-catenin pathways by inhibiting Akt and down-
regulating the PI3K pathway [94]. Inhibitors of Akt are
at the forefront of therapeutic intervention strategies that
promote anti-cancer effects in breast cancer. Zhu et al.
observed that AZD5363, an Akt inhibitor, was successful
in reducing stemness in the breast cancer cell line MCF-7.
It was used in combination with 3,3′-diindoylmethane to
induce apoptosis in the cells [95].
The dysregulation of the signal transducer 3 in cell plas-
ticity and therapy resistance in breast cancer makes it an
attractive target for small molecule inhibitors and drugs.
Resveratrol is a natural phytoalexin that regulates the cas-
cade of STAT signaling and has the potential to mitigate
breast cancer progression [96]. Studies have been con-
ducted in vitro that showed the target of Resveratrol is
STAT3 protein [97]. Resveratrol triggers a stepwise inhibi-
tion cascade involving Src tyrosine kinase and STAT3 pro-
teins. In order to circumvent the problem of trastuzumab
resistance in Her2+ patients, scientists have targeted the
proto-oncogene MUC1, which is a downstream target of
STAT3 [98]. 6Br-6a is a STAT3 inhibitor that decreased cell
proliferation, increased apoptosis and reduced plasticity
making it a promising target in breast cancer [99].
The use of molecules that inhibit the various con-
stituents of the Wnt signaling cascade is currently being
studied as a potential therapeutic strategy in Wnt-
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CHATTERJEE et al.
dependent cancers and as a mechanism to inhibit the
therapy resistance conferred by this oncogenic signaling
pathway. For example, the introduction of a truncated
version of the APC protein was shown to have mod-
erate success in mediating the degradation of β-catenin
in colorectal cancers where the APC gene has a loss-of-
function mutation [100]. Another potential mechanism
to increase β-catenin degradation involves the modula-
tion of Axin production through the active inhibition
of Tankyrases, which are proteins that degrade Axin.
Tankyrase inhibitors such as XAV939 strongly suppress
the Wnt/beta-catenin pathway, resulting in an anti-cancer
effect in Wnt-mediated cancers [101]. PAF-Wnt signaling
is involved in inducing cellular plasticity in breast cancer
cells and can be considered as a potential therapeutic tar-
get. In a study by Wang et al., PAF was evaluated as a target
of the Wnt pathway, and drugs were screened against the
pathway. NVP-AUY922, an Hsp90 inhibitor, leads to sig-
nificant downregulation of β-catenin, thus reducing the
stemness of the cancer cells.
The Hh pathway is a strong contender for therapeutic
targeting in breast cancer given its important role in the
progression of the disease by using Hh inhibitor molecules.
For example, SMO inhibitors that target the SMO recep-
tor have proved to be fairly successful. Two different
SMO inhibitors, vismodegib and sonidegib, have received
approval from the Food and Drug Administration (FDA)
for the treatment of breast cancer after it was found that
these molecules were able to successfully bind to SMO and
inhibit the downstream activation of the Hh target genes.
Novel SMO inhibitors such as saridegib and taladegib are
now under development, demonstrating the scope in the
area of SMO inhibitor-based treatment mechanisms for
several cancer types [102]. In addition, cyclin-dependent
kinase inhibitors such as dinaciclib targeting the Hh sig-
naling pathway are also currently being tested in clinical
trials as shown in a recent study leading to the reduction
of stemness and other malignant properties in TNBC cells
[103].
Targeted therapies involving the inhibition of the Notch
pathway in breast cancer are chiefly based on the use of
gamma-secretase inhibitors, transcriptional inhibitors,
and monoclonal antibodies, which target the ligand and
receptor components of the Notch pathway. In vitro
studies with ER+ breast cancer cells treated with the
gamma-secretase inhibitor Z-Leu-Leu-Nle-CHO [104] led
to the strong inhibition of cells and reduction of plasticity
of the cancer cells. Furthermore, a study using a TNBC
murine model showed that the inhibition of a deubiquiti-
nase USP9x using the small molecule inhibitor G9 reduces
Notch activity [105]. ϒ-secretase inhibitor MRK-003
reversed the role of Jagged-1-mediated bone metastasis
in cancer and consequently decreases tumor growth.
 26899655, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cso2.1051 by Nat Prov Indonesia, Wiley Online Library on [19/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CHATTERJEE et al. 9 of 15

TA B L E 1 Molecular pathways involved in cancer plasticity, which impact drug resistance and possible therapeutic strategies.
Pathway Related drug resistance Potential treatment Inhibitor targeted
MAPK pathway 1. Chemoresistance 1. CH5126766 along with eribulin 1. RAF/MEK inhibitor [89]
2. Radiation resistance 2. Dual inhibitors cobimetinib and 2. MEK1/2 and MEK 5 [90]
3. Enzyme therapy resistance trametinib 3. p38 pathway [91]
3. Brucein D
PI3K/AKT/mTOR 1. Chemotherapy Resistance 1. Gigantol 1. Akt [93]–[95]
pathway 2. Radiotherapy resistance 2. Anilide Shikonin ester- M9. 2. Luminal A breast cancer
3. AZD5363 alongside cells [119]
3,3′-Diindoylmethane
4. Dietary phytochemicals
STAT3 pathway 1. Radiotherapy resistance 1. Resveratrol 1. STAT3 [96, 98, 99]
2. Chemotherapy resistance 2. Trastuzumab
3. 6Br-6a
Wnt/β-catenin 1. Chemoresistance 1. Tankyrase inhibitors such as XAV939 1. Axin degradation [101]
pathway 2. Radioresistance 2. Introduction of truncated APC 2. Lack of APC [101]
3. Immunotherapy resistance 3. Targeting β-catenin 3. NVP-AUY922
Hedgehog pathway 1. Chemoresistance 1. SMO inhibitors like vismodegib, 1. SMO receptor [102, 103]
2. Immunotherapy resistance sonidegib, saridegib, and taladegib
Notch pathway 1. Chemoresistance 1. Gamma-secretase inhibitors such as 1. Gamma-secretase protein
2. Immunotherapy resistance Z-Leu-Leu-Nle-CHO [104, 105]
2. Monoclonal antibodies like OMP-59R5 2. Notch 2/ Notch 3 receptors
[120]
Abbreviations: AKT, Ak strain transforming; APC, adenomatous polyposis coli; MAPK, mitogen activated protein kinases; MEK, mitogen-activated protein kinase
kinase; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide-3-kinase; RAF, rapidly accelerated fibrosacroma; STAT3, signal transducer and activator
of transcription 3.

Different treatment avenues have been developed over
the years to target the deadly phenomenon of cellular
plasticity. Targeting the complex network of cell signaling
pathways to curb the phenomenon of resistance aris-
ing from cellular plasticity has led to different efficient
therapies. However, the complexity involved in cancer
cell plasticity is still to be uncovered completely and
newer targets explored to curb the scourge of therapeutic
resistance. (Table 1) (Figure 2)
5 CONCLUSION AND FUTURE
PERSPECTIVES
Interest in understanding cancer cell plasticity as well as its
crucial role in therapy resistance has led to the uncovering
of several mechanisms behind this process. The main focus
of this review is the cell-intrinsic pathways that modulate
the phenomenon of plasticity with the aim of targeting
major cell-intrinsic as well as extrinsic drivers of the pro-
cess. Cell intrinsic mechanisms include major signaling
pathways, which are mostly dysregulated in cancer lead-
ing to the ability of the cells to transition between different
phenotypes [13, 106]. These dysregulated pathways also
are a major driving factor for the development of resis-
tance toward treatment and targeting the same has been
the major focus of researchers for a long time.
Unfortunately, even with the advancement of therapy
targeting different pathways that facilitate cellular plas-
ticity, the prognosis has not improved much for patients.
Various hurdles in curbing the problem of cancer cell
plasticity and associated drug resistance remain. In depth
understanding of CSCs and their crosstalk with the TME
as well as role of the TME in pathway dysregulation and
its role in cancer cell plasticity is of foremost importance.
The TME [107] is a complex network of different cells,
which along with the cancer cells provide an avenue for
the induction of cellular plasticity as well as therapy resis-
tance. Targeting the microenvironment will also lead to
potential therapeutic avenues for curbing this deadly phe-
nomenon of plasticity and therapy resistance. The exact
mechanisms, both intrinsic and extrinsic mechanisms
leading to cancer cell plasticity and therapy resistance in
cancer, are yet to be untangled. This will be of immense
value to researchers who are continuously looking for
designing new therapeutic approaches that aim at perturb-
ing the interplay of cellular factors resulting in plasticity
[108] and therapy resistance.
Another area of development concerns the major set-
back that occurs with treatment strategies is clonal evo-
lution leading to acquired resistance against these tar-
geted therapies and inhibitors. One strategy to overcome
acquired resistance is to make next-generation inhibitors
that are able to target the resistance arising due to clonal
 26899655, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cso2.1051 by Nat Prov Indonesia, Wiley Online Library on [19/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
10 of 15 CHATTERJEE et al.

F I G U R E 2 Targeting molecular pathways contributing to cancer cell plasticity. Different therapeutic molecules and treatment
modalities that target pathways have been developed with the inhibitors having the potential to effect its target molecule and reversing
plasticity. MAPK: mitogen-activated protein kinases, Raf: Rapidly accelerated fibrosacroma, MEK 1: mitogen-activated protein kinase kinase,
STAT3: Signal transducer and activator of transcription 3, Akt: Ak strain transforming.

evolution. In a study by Hayashi et al., inhibitors of Epi-
dermal Growth Factor Receptors (EGFR) and anaplastic
lymphoma kinase were developed targeting the altered
phenotypes of the gene [109]. Various genetic mutations
in therapy-resistant cancer cells like BRAF, PTEN, MET,
and TP53 have been observed in colorectal cancer, which
are considered as clonal markers [110]. Studies to deter-
mine the reasons for these markers that lead to clonal
evolution of the tumor are in PTEN, ROBO1, CDH1,
PIK3CG, DMD, and LRP1B [111]. Targeting the geneti-
cally altered factors leading to clonal evolution through
precision medicine and personalized therapy can be an
alternative to overcome the barrier.
Computational approaches such as modeling the
dynamics of gene regulatory networks, metabolic model-
ing and machine learning are being increasingly used to
study tumor development and suggest new cancer treat-
ment strategies [112]. Metastatic castrate-resistant prostate
cancer progression involves a complex circuit involving
TGFβ and receptor activator of nuclear kappa β (κβ)
ligand, which have shown to possess multiple potential
therapeutic targets [113, 114]. To address the complexity
and multi-scale nature of the disease, initial predictions
were generated using discrete-continuum hybrid cellular
automata agent-based model; these predictions were later
validated using in vitro and in vivo studies [115]. In a
study involving breast-cancer-bearing mice, microscale
computed tomography images were compounded with a
multi-scale computational model to predict the growth
patterns of the microvascular networks and cancer cell
progression [116]. This multi-scale model included a
combination of partial differential equations, deep rein-
forcement learning and agent-based modeling. It helped
recreate patterns of tumor growth and the evolution of
microvascular network morphology by estimating the
gradient of factors like oxygen and Vascular Endothelial
Growth Factor (VEGF) along with the temporal changes
observed in the cellular phenotype. In a study involving
high-grade serous ovarian carcinoma, a mathemati-
cal model was used to determine the effectiveness of
treatment strategies such as initial surgery followed by
chemotherapy and multiple chemotherapy cycles [117].
Mathematical models have also been developed to study
therapeutic resistance during cancer treatment [118], such
as quantifying the role of point mutations, phenotypic
switching, gene amplification and the amount of drug
dosage accessible to cells in enabling drug resistance.
To conclude, we strongly believe that unraveling the
molecular circuitry involved in cancer cell plasticity lead-
ing to drug resistance will open new avenues of therapeutic
targeting, which will ultimately benefit patients.
AC K N OW L E D G M E N T S
The authors would like to acknowledge Ms Mubeena S for
her help with editing the paper. The authors would also
like to thank RGCB for funding.
D A T A AVA I L A B I L I T Y S T A T E M E N T
Data sharing is not applicable to this article as no datasets
were generated or analyzed during the current study.
 26899655, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cso2.1051 by Nat Prov Indonesia, Wiley Online Library on [19/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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How to cite this article: N. Chatterjee, B.
Pulipaka, A. R. Subbalakshmi, M. K. Jolly, and R.
Nair, Unraveling the dangerous duet between cancer
cell plasticity and drug resistance, Comput Syst
Oncol. 3 (2023), e1051.
https://doi.org/10.1002/cso2.1051