Genetic modifiers of EGFR dependence in non-small cell lung cancer.
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 EGFR-dependent 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.
|Year of Publication||
Proc Natl Acad Sci U S A
2014 Dec 30
|PubMed Central ID||
P50CA090578 / CA / NCI NIH HHS / United States
R01CA116020 / CA / NCI NIH HHS / United States
U54 HG006093 / HG / NHGRI NIH HHS / United States
R01CA109038 / CA / NCI NIH HHS / United States
R01 CA109038 / CA / NCI NIH HHS / United States
T32 CA009216 / CA / NCI NIH HHS / United States
P50 CA090578 / CA / NCI NIH HHS / United States
R01 CA116020 / CA / NCI NIH HHS / United States
5U54HG006093 / HG / NHGRI NIH HHS / United States