title: Genetic modifiers of EGFR dependence in non-small cell lung cancer.
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.
authors.affiliation: 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.
authors.forename: Tanaz
authors.initials: T
authors.lastname: Sharifnia
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142; Genetics and Medicine, Harvard Medical School, Boston, MA 02115;
authors.forename: Victor
authors.initials: V
authors.lastname: Rusu
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142;
authors.forename: Federica
authors.initials: F
authors.lastname: Piccioni
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142;
authors.forename: Mukta
authors.initials: M
authors.lastname: Bagul
authors.affiliation: 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.
authors.forename: Marcin
authors.initials: M
authors.lastname: Imielinski
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142;
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cherniack
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; and.
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Pedamallu
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142;
authors.forename: Bang
authors.initials: B
authors.lastname: Wong
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; and.
authors.forename: Frederick H
authors.initials: FH
authors.lastname: Wilson
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; and.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142;
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142;
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142;
authors.forename: Aravind
authors.initials: A
authors.lastname: Subramanian
authors.affiliation: 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 matthew_meyerson@dfci.harvard.edu.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D017231:Proto-Oncogene Proteins c-mos / Q000096:biosynthesis / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000096:biosynthesis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000096:biosynthesis / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000096:biosynthesis / Q000235:genetics; D020917:Receptor, trkA / Q000096:biosynthesis / Q000235:genetics; D020813:Receptor, trkB
chemical_list: D008562:Membrane Glycoproteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; D011505:Protein-Tyrosine Kinases; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D020917:Receptor, trkA; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human; C080813:emt protein-tyrosine kinase; D017231:Proto-Oncogene Proteins c-mos; D019908:Proto-Oncogene Proteins c-raf
keywords: ORF; epidermal growth factor receptor; non-small cell lung cancer