In vivo oncogenic conflict triggered by co-existing KRAS and EGFR activating mutations in lung adenocarcinoma

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 EGFR^L858R in advanced Kras^G12V-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 EGFR^L858R in Kras^G12V-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 EGFR^L858R expression. 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.