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

Nature Medicine volume 22, pages 262–269 (2016)Cite this article

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Abstract

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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Figure 1: Variable sensitivity of gefitinib-resistant EGFRT790M-positive PC9 cell lines to EGFR inhibition.
Figure 2: Early EGFRT790M-acquired resistance results from selection of pre-existing EGFRT790M clones.
Figure 3: Late-emerging EGFRT790M-acquired resistance results from evolution of drug-tolerant cells.
Figure 4: Late-evolving EGFRT790M-acquired resistance is associated with decreased apoptotic responses to EGFR inhibition.
Figure 5: Navitoclax enhances the apoptotic response of late-resistant EGFRT790M cells with decreased sensitivity to EGFR inhibition.

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Acknowledgements

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.).

Author information

Author notes

  1. Adam S Crystal

    Present address: Present address: Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.,

  2. Aaron N Hata and Matthew J Niederst: These authors contributed equally to this work.

Authors and Affiliations

  1. Massachusetts General Hospital (MGH) Cancer Center, Charlestown, Massachusetts, USA

    Aaron N Hata, Matthew J Niederst, Hannah L Archibald, Maria Gomez-Caraballo, Faria M Siddiqui, Hillary E Mulvey, Yosef E Maruvka, Haichuan Hu, Sana Raoof, Elizabeth Lockerman, Anuj Kalsy, Dana Lee, Leah J Damon, Adam S Crystal, Carlotta Costa, Zofia Piotrowska, Gad Getz, Lecia V Sequist & Jeffrey A Engelman

  2. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

    Aaron N Hata, Matthew J Niederst, Sana Raoof, Carlotta Costa, Zofia Piotrowska, Lecia V Sequist & Jeffrey A Engelman

  3. Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA

    Yosef E Maruvka & Gad Getz

  4. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA

    Fei Ji & Ruslan I Sadreyev

  5. Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA

    Hyo-eun C Bhang, Viveksagar Krishnamurthy Radhakrishna, Celina L Keating & Frank Stegmeier

  6. Department of Oncology, University of Torino, Torino, Italy

    Giulia Siravegna & Alberto Bardelli

  7. Candiolo Cancer Institute–Fondazione Piemontese per l′Oncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Candiolo, Italy

    Giulia Siravegna & Alberto Bardelli

  8. Translational Clinical Oncology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA

    David A Ruddy

  9. Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA

    Anthony J Iafrate, Ruslan I Sadreyev & Gad Getz

  10. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

    Gad Getz

  11. Virginia Commonwealth University Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry, Richmond, Virginia, USA

    Anthony C Faber

  12. Virginia Commonwealth University Massey Cancer Center, Richmond, Virginia, USA

    Anthony C Faber

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Contributions

A.N.H., M.J.N. and J.A.E. designed the study, analyzed the data and wrote the paper. A.N.H., M.J.N., H.L.A., M.G.-C., F.M.S., H.E.M., H.H. and L.J.D. performed cell line and biochemical studies. M.G.-C. and C.C. performed tumor xenograft studies. E.L., A.K. and D.L. generated the patient-derived cell lines. H.C.B., V.K.R., C.L.K., D.A.R. and F.S. performed barcode analysis. Y.E.M. and G.G. performed mathematical modeling of EGFRT790M evolution. F.J. and R.I.S. performed RNA-seq analysis. A.S.C. performed combination drug screening. G.S., A.J.I. and A.B. performed genotyping analysis. S.R. performed mathematical modeling of emergence of RFP-resistant clones. A.C.F. was involved with study design. L.V.S. and Z.P. provided EGFR-mutated NSCLC patient samples. A.N.H. and M.J.N. contributed equally to the study. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Jeffrey A Engelman.

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Competing interests

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). https://doi.org/10.1038/nm.4040

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