Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 26, Pages E6030-E6038Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1717782115
Keywords
YES1; EGFR; ALK; acquired resistance; lung adenocarcinoma
Categories
Funding
- National Institutes of Health (NIH)/National Cancer Institute (NCI) Grants [R01 CA120247, P01 CA129243, P30 CA008748]
- New York State Empire Clinical Research Investigator Program
- Lung Cancer Research Foundation
- Functional Genomics Initiative at MSKCC
- Katha Diddel Sussman & Warren Family Fund for Genome Research
- V Foundation Scholar-in-Training Award
- American Association of Cancer Research (AACR)-Genentech Career Development Award
- Damon Runyon Clinical Investigator Award
- LUNGevity Career Development Award
- NIH/NCI [R01 CA121210]
- Yale SPORE in Lung Cancer Grant [P50CA196530]
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In similar to 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 post-inhibitor 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 TK15. 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.
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