EGFR inhibition generates drug-tolerant persister cells by blocking AKT activity

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. We recently studied the mechanism by which a small subset of cells 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. These observations may explain why a small subset of quiescent cells can tolerate TKIs, leading to acquired drug resistance. In this editorial, we discuss how changes in intrinsic cell signaling open a new avenue to drug resistance in NSCLCs after EGFR inhibition. We also comment on combined treatment with TKI and MEK inhibitor to reduce the probability of emergent resistance to EGFR TKIs.