Research ArticleCancer

Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer

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Science Translational Medicine  18 Sep 2019:
Vol. 11, Issue 510, eaaw7999
DOI: 10.1126/scitranslmed.aaw7999

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Cutting off tumors’ escape routes

Cancer-driving mutations in the KRAS oncogene are common in many cancer types, including lung cancer. The combination of inhibitors for the kinases MEK and IGF1R is effective in KRAS-mutant lung cancer, but some cancer cells can still survive this treatment. Molina-Arcas et al. used an shRNA screening approach to identify another category of drugs that can be added to the therapeutic regimen to enhance its effectiveness. The authors then substituted an inhibitor of mutant KRAS to replace the MEK inhibitor in the combination to decrease treatment toxicity. The resulting triple-drug combination showed promising results in mouse models, with improved efficacy and tolerability.

Abstract

KRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using KRAS-G12C mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS mutations have been shown previously to be selectively sensitive to inhibition of mitogen-activated protein kinase kinase (MEK) and insulin-like growth factor 1 receptor (IGF1R) signaling. Here, we show that this effect is markedly enhanced by simultaneous inhibition of mammalian target of rapamycin (mTOR) while maintaining selectivity for the KRAS-mutant genotype. Combined mTOR, IGF1R, and MEK inhibition inhibits the principal signaling pathways required for the survival of KRAS-mutant cells and produces marked tumor regression in three different KRAS-driven lung cancer mouse models. Replacing the MEK inhibitor with the mutant-specific KRAS-G12C inhibitor ARS-1620 in these combinations is associated with greater efficacy, specificity, and tolerability. Adding mTOR and IGF1R inhibitors to ARS-1620 greatly improves its effectiveness on KRAS-G12C mutant lung cancer cells in vitro and in mouse models. This provides a rationale for the design of combination treatments to enhance the impact of the KRAS-G12C inhibitors, which are now entering clinical trials.

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