Abstract 877: Evolution of resistance to EGFR inhibition from drug tolerant cancer cells

Acquired drug resistance to targeted cancer therapies remains a significant clinical problem. Although mechanisms of acquired resistance of EGFR mutant non-small cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. We demonstrate that acquired resistance caused by the T790M gatekeeper mutation can occur either by selection of pre-existing T790M clones or via evolution of T790M-negative drug tolerant cells that develop the mutation during drug treatment. Additionally, the path to resistance impacts the biology of the resistant clone, as those that evolved from drug tolerant cells have a diminished apoptotic response to third generation EGFR inhibitors that target T790M EGFR. To characterize drug tolerant cells in patients undergoing EGFR inhibitor therapy, we performed single-cell RNA-Seq on EGFR mutant NSCLC samples prior to and after initiation of EGFR inhibitor. These results offer novel insights into the evolution of acquired resistance to EGFR inhibitors and point to new therapeutic opportunities to prevent or overcome resistance in the clinic. Citation Format: Aaron N. Hata, Yotam Drier, Maria Gomez-Caraballo, Faria Siddiqui, Lecia Sequist, Bradley Bernstein, Jeffrey Engelman. Evolution of resistance to EGFR inhibition from drug tolerant cancer cells. [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 877.