Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer

Hidenori Kitai, Philip H. Choi, Yu C. Yang, Jacob A. Boyer, Adele Whaley, Priya Pancholi, Claire Thant, Jason Reiter, Kevin Chen, Vladimir Markov, Hirokazu Taniguchi, Rui Yamaguchi, Hiromichi Ebi, James Evans, Jingjing Jiang, Bianca Lee, David Wildes, Elisa Stanchina, Jacqueline A. M. Smith, Mallika Singh () and Neal Rosen ()
Additional contact information
Hidenori Kitai: Memorial Sloan Kettering Cancer Center
Philip H. Choi: Memorial Sloan Kettering Cancer Center
Yu C. Yang: Revolution Medicines Inc.
Jacob A. Boyer: Memorial Sloan Kettering Cancer Center
Adele Whaley: Memorial Sloan Kettering Cancer Center
Priya Pancholi: Memorial Sloan Kettering Cancer Center
Claire Thant: Memorial Sloan Kettering Cancer Center
Jason Reiter: Memorial Sloan Kettering Cancer Center
Kevin Chen: Memorial Sloan Kettering Cancer Center
Vladimir Markov: Memorial Sloan Kettering Cancer Center
Hirokazu Taniguchi: Memorial Sloan Kettering Cancer Center
Rui Yamaguchi: Aichi Cancer Center Research Institute
Hiromichi Ebi: Aichi Cancer Center Research Institute
James Evans: Revolution Medicines Inc.
Jingjing Jiang: Revolution Medicines Inc.
Bianca Lee: Revolution Medicines Inc.
David Wildes: Revolution Medicines Inc.
Elisa Stanchina: Memorial Sloan Kettering Cancer Center
Jacqueline A. M. Smith: Revolution Medicines Inc.
Mallika Singh: Revolution Medicines Inc.
Neal Rosen: Memorial Sloan Kettering Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Current KRASG12C (OFF) inhibitors that target inactive GDP-bound KRASG12C cause responses in less than half of patients and these responses are not durable. A class of RASG12C (ON) inhibitors that targets active GTP-bound KRASG12C 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 KRASG12C inhibitor with a selective mTORC1 kinase inhibitor causes synergistic inhibition of Cyclin D1 expression and cap-dependent translation. Moreover, BIM upregulation by KRASG12C 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 KRASG12C-dependent lung cancer.

Date: 2024
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DOI: 10.1038/s41467-024-50063-z

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