Purpose: Despite the challenge to directly target mutant KRAS due to its high GTP affinity, some agents are under development against downstream signaling pathways, such as MEK inhibitors. However, it remains controversial whether MEK inhibitors can boost current chemotherapy in KRAS-mutant lung tumors in clinic. Considering the genomic heterogeneity among lung cancer patients, it is valuable to test potential therapeutics in KRAS-mutation driven mouse models. Experimental Design: We first compared the pERK1/2 level in lung cancer samples with different KRAS substitutions and generated a new genetically engineered mouse model whose tumor was driven by KRAS G12C, the most common KRAS mutation in lung cancer. Next, we evaluated the efficacy of selumetinib or its combination with chemotherapy, in KRAS G12C tumors compared to KRAS G12D tumors. Moreover, we generated KRAS G12C/p53 R270H model to explore the role of a dominant negative p53 mutation detected in patients in responsiveness to MEK inhibition. Results: We determined higher pERK1/2 in KRAS G12C lung tumors compared to KRAS G12D. Using mouse models, we further identified that KRAS G12C tumors are significantly more sensitive to selumetinib compared with Kras G12D tumors. MEK inhibition significantly increased chemotherapeutic efficacy and progression-free survival of KRAS G12C mice. Interestingly, p53 co-mutation rendered KRAS G12C lung tumors less sensitive to combination treatment with selumetinib and chemotherapy. Conclusions: Our data demonstrate that unique KRAS mutations and concurrent mutations in tumor-suppressor genes are important factors for lung tumor responses to MEK inhibitor. Our preclinical study supports further clinical evaluation of combined MEK inhibition and chemotherapy for lung cancer patients harboring KRAS G12C and wildtype p53 status.
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