Combined inhibition of KRAS G12C and mTORC1 kinase is synergistic in non-small cell lung cancer.

Autor: Kitai H; Program in Molecular Pharmacology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Choi PH; Program in Molecular Pharmacology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Yang YC; Department of Biology, Revolution Medicines Inc., Redwood City, CA, USA., Boyer JA; Program in Molecular Pharmacology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Whaley A; Program in Molecular Pharmacology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Pancholi P; Program in Molecular Pharmacology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Thant C; Program in Molecular Pharmacology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Reiter J; Program in Molecular Pharmacology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Chen K; Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Markov V; Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Taniguchi H; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Yamaguchi R; Division of Cancer Systems Biology, Aichi Cancer Center Research Institute, Nagoya, Aichi, 464-8681, Japan., Ebi H; Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Aichi, 464-8681, Japan., Evans J; Department of Biology, Revolution Medicines Inc., Redwood City, CA, USA., Jiang J; Department of Biology, Revolution Medicines Inc., Redwood City, CA, USA., Lee B; Department of Biology, Revolution Medicines Inc., Redwood City, CA, USA., Wildes D; Department of Biology, Revolution Medicines Inc., Redwood City, CA, USA., de Stanchina E; Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Smith JAM; Department of Biology, Revolution Medicines Inc., Redwood City, CA, USA., Singh M; Department of Biology, Revolution Medicines Inc., Redwood City, CA, USA. msingh@revmed.com., Rosen N; Program in Molecular Pharmacology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rosenn@mskcc.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 19; Vol. 15 (1), pp. 6076. Date of Electronic Publication: 2024 Jul 19.
DOI: 10.1038/s41467-024-50063-z
Abstrakt: Current KRAS G12C (OFF) inhibitors that target inactive GDP-bound KRAS G12C cause responses in less than half of patients and these responses are not durable. A class of RAS G12C (ON) inhibitors that targets active GTP-bound KRAS G12C blocks ERK signaling more potently than the inactive-state inhibitors. Sensitivity to either class of agents is strongly correlated with inhibition of mTORC1 activity. We have previously shown that PI3K/mTOR and ERK-signaling pathways converge on key cellular processes and that inhibition of both pathways is required for inhibition of these processes and for significant antitumor activity. We find here that the combination of a KRAS G12C inhibitor with a selective mTORC1 kinase inhibitor causes synergistic inhibition of Cyclin D1 expression and cap-dependent translation. Moreover, BIM upregulation by KRAS G12C inhibition and inhibition of MCL-1 expression by the mTORC1 inhibitor are both required to induce significant cell death. In vivo, this combination causes deep, durable tumor regressions and is well tolerated. This study suggests that the ERK and PI3K/mTOR pathways each mitigate the effects of inhibition of the other and that combinatorial inhibition is a potential strategy for treating KRAS G12C -dependent lung cancer.
(© 2024. The Author(s).)
Databáze: MEDLINE
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