YES1 Amplification Is a Mechanism of Acquired Resistance to EGFR Inhibitors Identified by Transposon Mutagenesis and Clinical Genomics

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • DNA Transposable Elements*
  • Drug Resistance, Neoplasm*
  • Enzyme Inhibitors / pharmacology*
  • ErbB Receptors* / antagonists & inhibitors
  • ErbB Receptors* / genetics
  • ErbB Receptors* / metabolism
  • Gene Amplification*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Proto-Oncogene Proteins c-fyn / genetics
  • Proto-Oncogene Proteins c-fyn / metabolism
  • Proto-Oncogene Proteins c-yes* / biosynthesis
  • Proto-Oncogene Proteins c-yes* / genetics
  • Proto-Oncogene Proteins pp60(c-src) / genetics
  • Proto-Oncogene Proteins pp60(c-src) / metabolism

Substances

  • DNA Transposable Elements
  • Enzyme Inhibitors
  • EGFR protein, human
  • ErbB Receptors
  • FYN protein, human
  • Proto-Oncogene Proteins c-fyn
  • Proto-Oncogene Proteins c-yes
  • Proto-Oncogene Proteins pp60(c-src)
  • YES1 protein, human