title: Evidence that synthetic lethality underlies the mutual exclusivity of oncogenic KRAS and EGFR mutations in lung adenocarcinoma.
abstract: Human lung adenocarcinomas (LUAD) contain mutations in EGFR in ∼15% of cases and in KRAS in ∼30%, yet no individual adenocarcinoma appears to carry activating mutations in both genes, a finding we have confirmed by re-analysis of data from over 600 LUAD. Here we provide evidence that co-occurrence of mutations in these two genes is deleterious. In transgenic mice programmed to express both mutant oncogenes in the lung epithelium, the resulting tumors express only one oncogene. We also show that forced expression of a second oncogene in human cancer cell lines with an endogenous mutated oncogene is deleterious. The most prominent features accompanying loss of cell viability were vacuolization, other changes in cell morphology, and increased macropinocytosis. Activation of ERK, p38 and JNK in the dying cells suggests that an overly active MAPK signaling pathway may mediate the phenotype. Together, our findings indicate that mutual exclusivity of oncogenic mutations may reveal unexpected vulnerabilities and therapeutic possibilities.
authors.affiliation: Cancer Biology Section, Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, United States.
authors.forename: Arun M
authors.initials: AM
authors.lastname: Unni
authors.affiliation: Cancer Biology Section, Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, United States.
authors.forename: William W
authors.initials: WW
authors.lastname: Lockwood
authors.affiliation: Cancer Biology Section, Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, United States.
authors.forename: Kreshnik
authors.initials: K
authors.lastname: Zejnullahu
authors.affiliation: Cancer Biology Section, Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, United States.
authors.forename: Shih-Queen
authors.initials: SQ
authors.lastname: Lee-Lin
authors.affiliation: Cancer Biology Section, Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, United States.
authors.forename: Harold
authors.initials: H
authors.lastname: Varmus
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*
chemical_list: C117307:KRAS protein, human; D050505:Mutant Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)
keywords: human; human biology; lung cancer; medicine; mouse; oncogenes; synthetic lethality