Unraveling lung cancer signaling pathways

Institution: Scripps Research Institute

Investigator(s):Jiing-Dwan Lee , Ph.D. -
Award
2006 (Cycle XV) Grant #: 15RT-0104 Award: $780,780
Cycle:
Subject
Cancer
Area:
Award Type:Research Project Awards
Initial Award Abstract
Lung cancer is among the most common and most deadly smoking-related cancer. Lung cancer
contributes to less than 30% of the smoking-attributable deaths. Existing therapies for lung
cancer are generally ineffective since the five-year survival rate for lung cancer patients has
stayed unchanged at 14% for the last twenty years. Recently, scientists have identified that
cigarette smoke contains various toxic chemicals whose motabolites bind to DNA and induce
activating point mutation in the K-ras gene. In fact, oncogenic mutations of the K-ras gene alone
can cause cancer and this mutation is found in 30% of human lung adenocarcinomas.
The oncogenic K-ras triggers a range of the intracellular signal transduction pathways leads to
lung tumorigenesis. With regard to this, others and we have found that the BMK1/ERK5 signaling
pathway is strongly activated in response to the expression of oncogenic ras as well as is
required for uncontrolled growth of lung cancer cells induced by oncogenic ras. To identify the
key components of the BMK1 signaling pathway that is critical for oncogenic ras induced
tumorigenesis, our lab has previously discovered essential regulatory molecules and molecular
targets for the BMK1 signaling pathway. Additionally, we have generated adenoviral vectors
encoding blockers that specifically suppress distinct steps of the BMK1-mediated oncogenic
signaling. These adenoviral vectors will be tested for their effectiveness in inhibiting lung tumor
development in lung cancer models. Importantly, our lab has recently developed animal models
allowed us to analyze the role of the BMK1 pathway in lung tumor initiation and progression as
well as to evaluate key elements in the BMK1 pathway as target(s) for lung cancer prevention
and therapy.
BMK1’s role in carcinogenesis is not limited to its contribution to the malignant nature of tumor
cells. Recently, data generated from BMK1-deficient mice (from us and two other labs) revealed
that BMK1 is critical for new blood vessel formation during development. Since angiogenesis
contributes to the pathological process of tumor growth, we hypothesize that BMK1 activity is also
involved in pulmonary tumor-induced neovascularization, which is vital for sustaining lung tumor
growth. As such, most recently, my lab has published results describing the important role of the
BMK1 pathway in lung tumor-induced angiogenesis, which suggests that intervention in this
kinase cascade could represent a practical and effective approach to deterring the development
of lung tumor.
Herein we propose to study the role of deregulated BMK1 pathway for lung tumor initiation and
progression as well as identifying and evaluating the critical elements in this signaling pathway as
target(s) for lung cancer prevention and therapy. Importantly, strategies to prevent or cure lung
cancer through blocking this oncogenic BMK1 pathway could be examined quite promptly and
precisely using our lung cancer models along with adenoviral vectors encoding blockers specific
for the BMK1 pathway. In combination, these studies will likely yield novel and important targets
for a more effective and specific therapeutic intervention for lung cancer.
Small cell lung carcinoma (SCLC) is a highly aggressive neoplasm, which accounts for
approximately 20% of all lung cancer cases. Molecular mechanisms altered in SCLC inc
induced expression of oncogene, MYC, and loss of tumorsuppressor genes, such as p53
RB, and FHIT. The overexpression of MYC proteins in SCLC is largely a result of gene
amplification. Such overexpression leads to more rapid proliferation and loss of termina
differentiation. Mutation or deletion of p53 or PTEN can lead to more rapid proliferation
reduced apoptosis. The retinoblastoma gene RB1 encodes a nuclear phosphoprotein th
to regulate cell-cycle progression. The fragile histidine triad gene FHIT encodes the enz
diadenosine triphosphate hydrolase, which is thought to have an indirect role in proapo
and cell-cycle control.

Reference pathway