title: In vivo oncogenic conflict triggered by co-existing KRAS and EGFR activating mutations in lung adenocarcinoma.
abstract: Activating mutations in KRAS and EGFR, the two most frequent oncogenes in human lung adenocarcinoma, are mutually exclusive, a phenotype attributed to functional redundancy implying lack of positive selection. Employing a mouse model expressing EGFRL858Rin advanced KrasG12V-driven tumors we show that their mutual exclusivity can be explained by detrimental effects of their co-expression in lung adenocarcinoma. In vivo, expression of EGFRL858Rin KrasG12V-driven tumors triggers replicative stress and apoptosis, while the surviving cells enter a transient cytostatic state incompatible with tumor development that is fully reversible upon discontinued EGFRL858Rexpression. Eventually, sustained expression of both mutants induces attenuation of oncogenic signaling to levels compatible with proliferation and tumor growth resulting in high sensitivity to Mek inhibition. Our results indicate that the mutual exclusivity of KRAS and EGFR mutations occurs as a combination of cellular toxicity and signal adjustment resulting in lack of selective advantage for cells expressing both oncogenes.
authors: Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors: C
authors: C
authors: Ambrogio
authors: Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors: M
authors: M
authors: Barbacid
authors: Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors: D
authors: D
authors: Santamaría
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: C541485:EGFR protein, mouse; D066246:ErbB Receptors; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)