Abstract
Mutations in KRAS are among the most frequent RAS alterations in human cancers and the prevalent driver event in lung adenocarcinoma (LUAD). Specific KRAS G12C inhibitors are showing very promising results in clinical trials. Small-molecule inhibitors of the MAPK pathway, one of the prominent downstream KRAS mediators, showed minimal clinical activity either as single agents or in combination with chemotherapy. We observed that loss of wild-type KRAS enhances tumor fitness in KRAS mutant cancer cells while concomitantly increasing sensitivity to MEK inhibitors and G12C inhibitors. Given the challenges of reanalyzing prior clinical trials, future clinical studies of targeted inhibitors should evaluate and/or stratify patients based on the relative expression of wild-type and mutant KRAS alleles to determine their correlation with treatment outcome. KRAS LOH, biomarkers, MAPK inhibition
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