IA02 Insights into KRAS Biology to Identify Potential Therapeutic Strategies

Abstract

Mutations in KRAS are among the most frequent RAS alterations in human cancers and the prevalent driver event in lung adenocarcinoma (LUAD). There are still no effective targeted therapies for KRAS-driven LUAD, although 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 inhibition. 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. We also showed that dimerization/oligomerization between KRAS proteins is a key regulator for lung adenocarcinoma biology and determinant of treatment response. We generated an inducible system to force either wild-type/mutant or mutant/mutant KRAS dimerization, which showed that forced dimerization between wild-type/mutant KRAS resulted in impaired cell growth as compared to forced mutant/mutant KRAS dimerization. Loss of wild-type KRAS enhances tumor fitness in KRAS mutant cancer cells while concomitantly increasing sensitivity to MEK inhibition. Dimerization of wild-type KRAS with mutant KRAS results in growth inhibition and changes the therapeutic index for MEK inhibitors. Mutant-mutant KRAS dimerization is critical for the full oncogenic properties of mutant KRAS. Collectively these observations suggest that strategies designed to interfere with KRAS dimerization should be evaluated as a therapeutic approach in KRAS mutant cancers.