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Contributed by Harold Varmus, May 8, 2018 (sent for review October 12, 2017; reviewed by Levi Garraway and Alice T. Shaw)
Significance
Despite high response rates to treatment with small molecule inhibitors of EGFR tyrosine kinase activity, patients with EGFR-mutant lung adenocarcinomas eventually develop resistance to these drugs. In many cases, the basis of acquired resistance remains unclear. We have used a transposon mutagenesis screen in an EGFR-mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify amplification of YES1 as a targetable mechanism of resistance to EGFR inhibitors in EGFR-mutant lung cancers.
Abstract
In ∼30% of patients with EGFR-mutant lung adenocarcinomas whose disease progresses on EGFR inhibitors, the basis for acquired resistance remains unclear. We have integrated transposon mutagenesis screening in an EGFR-mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify mechanisms of resistance to EGFR inhibitors. The most prominent candidate genes identified by insertions in or near the genes during the screen were MET, a gene whose amplification is known to mediate resistance to EGFR inhibitors, and the gene encoding the Src family kinase YES1. Cell clones with transposon insertions that activated expression of YES1 exhibited resistance to all three generations of EGFR inhibitors and sensitivity to pharmacologic and siRNA-mediated inhibition of YES1. Analysis of clinical genomic sequencing data from cases of acquired resistance to EGFR inhibitors revealed amplification of YES1 in five cases, four of which lacked any other known mechanisms of resistance. Preinhibitor samples, available for two of the five patients, lacked YES1 amplification. None of 136 postinhibitor samples had detectable amplification of other Src family kinases (SRC and FYN). YES1 amplification was also found in 2 of 17 samples from ALK fusion-positive lung cancer patients who had progressed on ALK TKIs. Taken together, our findings identify acquired amplification of YES1 as a recurrent and targetable mechanism of resistance to EGFR inhibition in EGFR-mutant lung cancers and demonstrate the utility of transposon mutagenesis in discovering clinically relevant mechanisms of drug resistance.
Footnotes
- ↵1To whom correspondence may be addressed. Email: fanp{at}mskcc.org, varmus{at}med.cornell.edu, or ladanyim{at}mskcc.org.
↵2Present address: Girihlet Inc., Oakland, CA 94609.
↵3Present address: Department of Translational Science, Personal Genome Diagnostics, Baltimore, MD 21224.
↵4Present address: Department of Medical Oncology, University Hospital Waterford, Waterford X91 ER8E, Ireland.
↵5Present address: Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105.
↵6Present address: Gene Editing Technologies Group, Oxford Genetics, Oxford OX4 4GA, United Kingdom.
↵7Present addresses: Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065; and New York Genome Center, New York, NY 10013.
This work was presented in part at the Annual Meeting of the American Society of Clinical Oncology, Chicago, June 2–6, 2017.
Author contributions: P.-D.F., K.P., H.V., and M.L. designed research; P.-D.F., G.N., A.D.J., E.V., P.S., H.A.Y., E.J.J., P.K.P., Y.Y.J., J.E.C., L.W., A.A.J., S.M., L.S., H.Q., and G.J.R. performed research; P.-D.F., G.N., A.D.J., N.R., P.S., S.G., and H.Q. contributed new reagents/analytic tools; P.-D.F., G.N., A.D.J., N.R., P.S., S.M., C.M.L., M.G.K., and M.L. analyzed data; and P.-D.F., C.M.L., K.P., H.V., and M.L. wrote the paper.
Reviewers: L.G., Eli Lilly; and A.T.S., Massachusetts General Hospital.
Conflict of interest statement: H.A.Y. has served on the advisory boards for AstraZeneca and Boehringer Ingelheim. Y.Y.J. has received consulting fees from Bristol–Myers Squibb and honoraria from Pfizer, Genentech, and Boehringer Ingelheim. J.E.C. has received consulting fees from AstraZeneca, Genentech, Bristol–Myers Squibb, and Merck. M.G.K. has served as a consultant for AstraZeneca. C.M.L. has served on the Advisory Board for Cepheid Oncology and has received consulting fees from Pfizer, Novartis, AstraZeneca, Genoptix, Sequenom, Ariad, Takeda, and Foundation Medicine. G.J.R. has received consulting fees from Roche, and Memorial Sloan Kettering Cancer Center (MSKCC) has received support from Pfizer and Roche to fund G.J.R.’s clinical research. K.P. has received research funding from AstraZeneca, Roche, Kolltan, and Symphogen; honoraria for consulting or advisory roles from AstraZeneca, Merck, Novartis, and Tocagen; and royalties from intellectual property licensed by MSKCC to Molecular MD. M.L. has received advisory board compensation from Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Takeda, and Bayer, and research support from LOXO Oncology.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1717782115/-/DCSupplemental.
- Copyright © 2018 the Author(s). Published by PNAS.
This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
YES1 amplification is a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics
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