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

Molina-Arcas, M; Moore, C; Rana, S; Van Maldegem, F; Mugarza, E; Romero-Clavijo, P; Herbert, E; Horswell, S; Li, L-S; Janes, M R; Hancock, D C; Downward, J

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.

Citation

Molina-Arcas, M., Moore, C., Rana, S., Van Maldegem, F., Mugarza, E., Romero-Clavijo, P., Herbert, E., Horswell, S., Li, L.-S., Janes, M. R., Hancock, D. C., & Downward, J. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Science Translational Medicine, https://doi.org/10.1126/scitranslmed.aaw7999

• Journal Article Type: Other
• Deposit Date: Oct 5, 2019
• Journal: Science Translational Medicine
• Print ISSN: 1946-6234
• Electronic ISSN: 1946-6242
• Publisher: American Association for the Advancement of Science
• DOI: https://doi.org/10.1126/scitranslmed.aaw7999
• Public URL: https://rvc-repository.worktribe.com/output/1384782