Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC
Katherine R. Amato, … , Nathanael S. Gray, Jin Chen
Katherine R. Amato, … , Nathanael S. Gray, Jin Chen
Published April 8, 2014
Citation Information: J Clin Invest. 2014;124(5):2037-2049. https://doi.org/10.1172/JCI72522.
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Research Article Oncology

Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC

Abstract

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.

Authors

Katherine R. Amato, Shan Wang, Andrew K. Hastings, Victoria M. Youngblood, Pranav R. Santapuram, Haiying Chen, Justin M. Cates, Daniel C. Colvin, Fei Ye, Dana M. Brantley-Sieders, Rebecca S. Cook, Li Tan, Nathanael S. Gray, Jin Chen

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Figure 1

Loss of EphA2 results in decreased tumor burden in a KrasG12D knockin mouse model of spontaneous NSCLC.

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Loss of EphA2 results in decreased tumor burden in a KrasG12D knockin mo...
(A) Lungs of wild-type and EphA2-deficient mice were collected, and the total lung weight was measured at 15, 20, and 25 weeks of age to assess the additional mass contributed to the lungs by the tumor burden. Average lung weight ± SEM is shown (n = 10 per genotype). (B) Tumor area on the lung surface was measured by a digital caliper and presented as average lung tumor surface area ± SEM (n = 8 per genotype). (C) Wild-type and EphA2-deficient KrasG12D mice were subjected to MRI at 15, 20, 25 weeks of age. T2-weighted MRI images were taken in the axial plane with slice thickness of 1 mm. Representative images at 15, 20, and 25 weeks are shown. White arrows indicate tumor tissue. H, heart; S, spine. (D) Tumor volumes were quantified as a composite of 10 serial MRI slices of the lung per mouse using Matlab software and were graphed as a tumor burden index relative to 15 weeks ± SEM (n = 5 per genotype). *P < 0.05.