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Significance So far, no targeted therapy has been approved for KRAS mutant tumors. We report that combined genetic inactivation of CDK4 and RAF1 in advanced KRAS/p53 mutant lung tumors leads to effective tumor regression without inducing significant toxicities. In spite of this therapeutic response, CDK4/RAF1-resistant cells appeared. We have identified and pharmacologically validated two independent resistance mechanisms involving hypermethylation of tumor-suppressor genes and activation of the PI3K pathway.

Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas