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

ABSTRACT: 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.

SUBMITTER: Kitai H

PROVIDER: S-EPMC11258147 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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

Kitai Hidenori H Choi Philip H PH Yang Yu C YC Boyer Jacob A JA Whaley Adele A Pancholi Priya P Thant Claire C Reiter Jason J Chen Kevin K Markov Vladimir V Taniguchi Hirokazu H Yamaguchi Rui R Ebi Hiromichi H Evans James J Jiang Jingjing J Lee Bianca B Wildes David D de Stanchina Elisa E Smith Jacqueline A M JAM Singh Mallika M Rosen Neal N

Nature communications 20240719 1

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 ...[more]

PMID: 39025835

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Project description:BackgroundNo therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C.MethodsWe conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.ResultsA total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.ConclusionsSotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

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

Publications

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

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

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Combined inhibition of KRAS&lt;sup&gt;G12C&lt;/sup&gt; and mTORC1 kinase is synergistic in non-small cell lung cancer.

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OmicsDI is part of the ELIXIR infrastructure

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

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