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

• Published in: Science translational medicine 2019-09, Vol.11 (510)
• Main Authors: Molina-Arcas, Miriam, Moore, Christopher, Rana, Sareena, van Maldegem, Febe, Mugarza, Edurne, Romero-Clavijo, Pablo, Herbert, Eleanor, Horswell, Stuart, Li, Lian-Sheng, Janes, Matthew R., Hancock, David C., Downward, Julian
• Format: Article
• Language: English
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.aaw7999

KRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using G12C KRAS mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS mutations have been shown previously to be selectively sensitive to inhibition of MEK and IGF1R signaling. Here we show that this effect is markedly enhanced by simultaneous inhibition of 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 G12C KRAS 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 G12C KRAS inhibitors which are now entering clinical trials.