EPHA2 blockade overcomes acquired resistance to EGFR kinase inhibitors in lung cancer

KR Amato, S Wang, L Tan, AK Hastings, W Song… - Cancer research, 2016 - AACR
KR Amato, S Wang, L Tan, AK Hastings, W Song, CM Lovly, CB Meador, F Ye, P Lu
Cancer research, 2016AACR
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 overexpressed in EGFR TKI-
resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells …
Abstract
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 overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFRT790M mutations in vitro and inhibited tumor growth and progression in an inducible EGFRL858R+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. Cancer Res; 76(2); 305–18. ©2016 AACR.
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