Journal
CANCER RESEARCH
Volume 76, Issue 2, Pages 305-318Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-15-0717
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Funding
- Department of Veterans Affairs through a VA Merit Award
- Department of Defense [W81XWH-14-1-0181]
- NIH [R01 CA95004, CA177681, CA173469, CA121210, P01 CA129243, U54 CA143798, F31 CA167878, CA68485, DK20593, DK58404, DK59637, EY08126]
- Damon Runyon Clinical Investigator Award
- LUNGevity Career Development Award
- Melley Family Scholarship
- VICC Thoracic Center
- Astra Zeneca
- NCI Cancer Center Support Grant [P30 CA068485]
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Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is over-expressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFR(T790M) mutations in vitro and inhibited tumor growth and progression in an inducible EGFR(L858R_T790M)-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors. (C) 2016 AACR.
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