Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFRT790M gatekeeper mutation can occur either by selection of pre-existing EGFRT790M-positive clones or via genetic evolution of initially EGFRT790M-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFRT790M; treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor–resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.
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We thank C. Benes and all members of the Engelman and Benes laboratories for helpful discussions and feedback. This study was funded by support from the US National Institutes of Health (NIH) (grant R01CA137008; J.A.E.), the Department of Defense (L.V.S. and J.A.E.), LunGevity (L.V.S. and J.A.E.), Uniting Against Lung Cancer (A.N.H. and M.J.N.), the Conquer Cancer Foundation of the American Society of Clinical Oncology (A.N.H.), the Lung Cancer Research Foundation (M.J.N.), Targeting a Cure for Lung Cancer (J.A.E.), Be a Piece of the Solution (J.A.E.), and the John and Carol Barry Foundation (A.N.H.).
J.A.E. is a consultant for Novartis, Sanofi, Genentech, Clovis and Astra Zeneca; owns equity in Gatekeeper Pharmaceuticals, which has interest in EGFRT790M inhibitors; and has research agreements with Novartis and AstraZeneca. A.N.H. has provided consulting services for Amgen. M.J.N. has provided consulting services for Boehringer Ingelheim Pharmaceuticals. Z.P. has provided consulting services for Clovis Oncology and Boehringer Ingelheim Pharmaceuticals. L.V.S. has provided uncompensated consulting services to Clovis Oncology, AstraZeneca, Novartis, Boehringer Ingelheim Pharmaceuticals, Merrimack Pharmaceuticals, Genentech and Taiho Pharmaceuticals. H.C.B., V.K.R., C.L.K., D.A.R., A.S.C. and F.S. are employees of Novartis, Inc., as noted in the affiliations.
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Hata, A., Niederst, M., Archibald, H. et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med 22, 262–269 (2016) doi:10.1038/nm.4040
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