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

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Date
2019-09ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Animals
Mice, Nude
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Imidazoles
Pyrazines
Pyridones
Pyrimidinones
Mitogen-Activated Protein Kinase Kinases
Receptor, IGF Type 1
RNA, Small Interfering
Antineoplastic Combined Chemotherapy Protocols
Protein Kinase Inhibitors
Signal Transduction
Cell Survival
Mutation
Proto-Oncogene Proteins p21(ras)
Proto-Oncogene Proteins c-akt
Phosphatidylinositol 3-Kinases
TOR Serine-Threonine Kinases
Research team
Lung Cancer Group
Language
eng
Date accepted
2019-08-09
License start date
2019-09
Citation
Science translational medicine, 2019, 11 (510)
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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