Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer.
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Embargo End Date
ICR Authors
Authors
Molina-Arcas, M
Moore, C
Rana, S
van Maldegem, F
Mugarza, E
Romero-Clavijo, P
Herbert, E
Horswell, S
Li, L-S
Janes, MR
Hancock, DC
Downward, J
Moore, C
Rana, S
van Maldegem, F
Mugarza, E
Romero-Clavijo, P
Herbert, E
Horswell, S
Li, L-S
Janes, MR
Hancock, DC
Downward, J
Document Type
Journal Article
Date
2019-09
Date Accepted
2019-08-09
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
Science translational medicine, 2019, 11 (510)
Source Title
Publisher
ISSN
1946-6234
eISSN
1946-6242
Collections
Research Team
Lung Cancer Group