Rebecca Cook
Faculty Member
Last active: 4/15/2019

Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC.

Amato KR, Wang S, Hastings AK, Youngblood VM, Santapuram PR, Chen H, Cates JM, Colvin DC, Ye F, Brantley-Sieders DM, Cook RS, Tan L, Gray NS, Chen J
J Clin Invest. 2014 124 (5): 2037-49

PMID: 24713656 · PMCID: PMC4001547 · DOI:10.1172/JCI72522

Genome-wide analyses determined previously that the receptor tyrosine kinase (RTK) EPHA2 is commonly overexpressed in non-small cell lung cancers (NSCLCs). EPHA2 overexpression is associated with poor clinical outcomes; therefore, EPHA2 may represent a promising therapeutic target for patients with NSCLC. In support of this hypothesis, here we have shown that targeted disruption of EphA2 in a murine model of aggressive Kras-mutant NSCLC impairs tumor growth. Knockdown of EPHA2 in human NSCLC cell lines reduced cell growth and viability, confirming the epithelial cell autonomous requirements for EPHA2 in NSCLCs. Targeting EPHA2 in NSCLCs decreased S6K1-mediated phosphorylation of cell death agonist BAD and induced apoptosis. Induction of EPHA2 knockdown within established NSCLC tumors in a subcutaneous murine model reduced tumor volume and induced tumor cell death. Furthermore, an ATP-competitive EPHA2 RTK inhibitor, ALW-II-41-27, reduced the number of viable NSCLC cells in a time-dependent and dose-dependent manner in vitro and induced tumor regression in human NSCLC xenografts in vivo. Collectively, these data demonstrate a role for EPHA2 in the maintenance and progression of NSCLCs and provide evidence that ALW-II-41-27 effectively inhibits EPHA2-mediated tumor growth in preclinical models of NSCLC.

MeSH Terms (16)

Animals Apoptosis Carcinoma, Non-Small-Cell Lung Cell Line, Tumor Cell Survival Heterografts Humans Lung Neoplasms Mice Mice, Knockout Neoplasm Proteins Neoplasm Transplantation Protein Kinase Inhibitors Receptor, EphA2 Ribosomal Protein S6 Kinases, 70-kDa Ribosomal Protein S6 Kinases, 90-kDa

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