Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition

Aaron N. Hata, Matthew J. Niederst, Hannah L. Archibald, Maria Gomez-Caraballo, Faria M. Siddiqui, Hillary E. Mulvey, Yosef E. Maruvka, Fei Ji, Hyo Eun C Bhang, Viveksagar Krishnamurthy Radhakrishna, Giulia Siravegna, Haichuan Hu, Sana Raoof, Elizabeth Lockerman, Anuj Kalsy, Dana Lee, Celina L. Keating, David A. Ruddy, Leah J. Damon, Adam S. CrystalCarlotta Costa, Zofia Piotrowska, Alberto Bardelli, Anthony J. Iafrate, Ruslan I. Sadreyev, Frank Stegmeier, Gad Getz, Lecia V. Sequist, Anthony C. Faber, Jeffrey A. Engelman

Research output: Contribution to journalArticlepeer-review


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 EGFR T790M gatekeeper mutation can occur either by selection of pre-existing EGFR T790M -positive clones or via genetic evolution of initially EGFR T790M -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 EGFR T790M; 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.

Original languageEnglish
Pages (from-to)262-269
Number of pages8
JournalNature Medicine
Issue number3
Publication statusPublished - Mar 1 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)


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