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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


M Molina-Arcas

C Moore

S Rana

F Van Maldegem

E Mugarza

P Romero-Clavijo

E Herbert

S Horswell

L-S Li

M R Janes

D C Hancock

J Downward


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.


Molina-Arcas, M., Moore, C., Rana, S., Van Maldegem, F., Mugarza, E., Romero-Clavijo, P., …Downward, J. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Science Translational Medicine,

Journal Article Type Other
Deposit Date Oct 5, 2019
Journal Science Translational Medicine
Print ISSN 1946-6234
Publisher American Association for the Advancement of Science
Public URL