In non-small-cell lung cancer (NSCLC)—the leading cause of cancer death worldwide—about 10-20% harbor mutations in epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK). Although treatment with EGFR tyrosine kinase inhibitors (TKIs) had shown promise, drug resistance has been the most important determinant limiting its success. Recent studies have identified the mechanisms of drug resistance to TKIs, but the origin of acquired resistant cells remains to be elucidated. We consider that they must arise from a small subset of surviving populations after EGFR inhibition. Thus, we have studied the mechanism by which the subset remains viable after EGFR inhibition, despite cell death in the vast majority. Our study demonstrates that EGFR inhibition in lung cancer cells generates a drug-tolerant subpopulation by blocking AKT activity and thus inactivating Ets-1 function. The remaining cells enter a dormant, non-dividing state because of the inhibited transactivation of Ets-1 target genes cyclins D1, D3, and E2. Moreover, Ets-1 inactivation inhibits transcription of dual specificity phosphatase 6 (DUSP6), a negative regulator specific for ERK1/2. As a result, ERK1/2 is activated, which combines with c-Src to renew activation of the Ras/MAPK pathway, causing increased cell survival by accelerating Bim protein turnover. Conversely, inhibition of elevated ERK1/2 by the addition of a MEK inhibitor enhances programmed cell death through rewiring apoptotic signaling. These observations may explain why a small subset of quiescent cells can tolerate TKIs, and might suggest that combined treatment of TKI and MEK inhibitor could overcome drug resistance in the population.

Citation Format: Janyaporn Phuchareon, David W. Eisele, Frank McCormick, Osamu Tetsu. EGFR inhibition generates drug-tolerant persister cells by blocking AKT activity and thus inactivating Ets-1 function. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 293.