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

doi:10.1073/pnas.1412228112

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

Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18661-6. doi: 10.1073/pnas.1412228112. Epub 2014 Dec 15.

Authors

Affiliations

¹ Broad Institute of Harvard and MIT, Cambridge, MA 02142; Departments of Pathology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; and.
² Broad Institute of Harvard and MIT, Cambridge, MA 02142; Genetics and Medicine, Harvard Medical School, Boston, MA 02115;
³ Broad Institute of Harvard and MIT, Cambridge, MA 02142;
⁴ Broad Institute of Harvard and MIT, Cambridge, MA 02142; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; and.
⁵ Broad Institute of Harvard and MIT, Cambridge, MA 02142; Genetics and Medicine, Harvard Medical School, Boston, MA 02115; Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114.
⁶ Broad Institute of Harvard and MIT, Cambridge, MA 02142; Departments of Pathology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; and [email protected].

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 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.

Keywords: ORF; epidermal growth factor receptor; non-small cell lung cancer.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Carcinoma, Non-Small-Cell Lung / enzymology*
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
ErbB Receptors / biosynthesis*
ErbB Receptors / genetics
Gene Expression Regulation, Enzymologic*
Gene Expression Regulation, Neoplastic*
Humans
Lung Neoplasms / enzymology*
Lung Neoplasms / genetics
Lung Neoplasms / pathology
MAP Kinase Signaling System*
Membrane Glycoproteins / biosynthesis
Membrane Glycoproteins / genetics
Protein-Tyrosine Kinases / biosynthesis
Protein-Tyrosine Kinases / genetics
Proto-Oncogene Proteins c-mos / biosynthesis
Proto-Oncogene Proteins c-mos / genetics
Proto-Oncogene Proteins c-raf / biosynthesis
Proto-Oncogene Proteins c-raf / genetics
Receptor Protein-Tyrosine Kinases / biosynthesis
Receptor Protein-Tyrosine Kinases / genetics
Receptor, Fibroblast Growth Factor, Type 1 / biosynthesis
Receptor, Fibroblast Growth Factor, Type 1 / genetics
Receptor, Fibroblast Growth Factor, Type 2 / biosynthesis
Receptor, Fibroblast Growth Factor, Type 2 / genetics
Receptor, trkA / biosynthesis
Receptor, trkA / genetics
Receptor, trkB

Substances

Membrane Glycoproteins
EGFR protein, human
ErbB Receptors
FGFR1 protein, human
FGFR2 protein, human
Protein-Tyrosine Kinases
RON protein
Receptor Protein-Tyrosine Kinases
Receptor, Fibroblast Growth Factor, Type 1
Receptor, Fibroblast Growth Factor, Type 2
Receptor, trkA
Receptor, trkB
tropomyosin-related kinase-B, human
emt protein-tyrosine kinase
Proto-Oncogene Proteins c-mos
Proto-Oncogene Proteins c-raf

Abstract

Publication types

MeSH terms

Substances

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