Genetic modifiers of EGFR dependence in non-small cell lung cancer

Tanaz Sharifnia, Victor Rusu, Federica Piccioni, Mukta Bagul, Marcin Imielinski, Andrew D. Cherniack, Chandra Sekhar Pedamallu, Bang Wong, Frederick H. Wilson, Levi A. Garraway, David Altshuler, Todd R. Golub, David E. Root, Aravind Subramanian, Matthew Meyerson

Research output: Contribution to journalArticlepeer-review

Abstract

Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor (EGFR) represent a common molecular subset of non-small cell lung cancer (NSCLC) cases. EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and thus represent a dependency in NSCLCs harboring these alterations, but the genetic basis of EGFR dependence is not fully understood. Here, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR-mutant NSCLC cells. This approach identified 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFRdependent PC9 cells, and these genes include seven of nine Src family kinase genes, FGFR1, FGFR2, ITK, NTRK1, NTRK2, MOS, MST1R, and RAF1. A subset of these genes can complement loss of EGFR activity across multiple EGFR-dependent models. Unbiased gene-expression profiling of cells overexpressing EGFR bypass genes, together with targeted validation studies, reveals EGFR-independent activation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes. Together, these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival.

Original languageEnglish (US)
Pages (from-to)18661-18666
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number52
DOIs
StatePublished - Dec 30 2014
Externally publishedYes

Keywords

  • Epidermal growth factor receptor
  • Non-small cell lung cancer
  • ORF

ASJC Scopus subject areas

  • General

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