Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer.
van Maldegem, F
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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.
Carcinoma, Non-Small-Cell Lung
Mitogen-Activated Protein Kinase Kinases
Receptor, IGF Type 1
RNA, Small Interfering
Antineoplastic Combined Chemotherapy Protocols
Protein Kinase Inhibitors
Proto-Oncogene Proteins p21(ras)
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Lung Cancer Group
License start date
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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