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Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):E6030-E6038. doi: 10.1073/pnas.1717782115. Epub 2018 Jun 6.

YES1 amplification is a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics.

Author information

1
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065; fanp@mskcc.org varmus@med.cornell.edu ladanyim@mskcc.org.
2
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
3
Computational Biology, New York Genome Center, New York, NY 10013.
4
Technology Innovation Lab, New York Genome Center, New York, NY 10013.
5
Project Management, New York Genome Center, New York, NY 10013.
6
Sequencing Operations, New York Genome Center, New York, NY 10013.
7
Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
8
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
9
Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232.
10
Department of Pathology and the Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520.
11
Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065 fanp@mskcc.org varmus@med.cornell.edu ladanyim@mskcc.org.

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.

KEYWORDS:

ALK; EGFR; YES1; acquired resistance; lung adenocarcinoma

PMID:
29875142
PMCID:
PMC6042104
DOI:
10.1073/pnas.1717782115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

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.

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