Combined inhibition of KRAS(G12C) and mTORC1 kinase is synergistic in non-small cell lung cancer Journal Article
| Authors: | Kitai, H.; Choi, P. H.; Yang, Y. C.; Boyer, J. A.; Whaley, A.; Pancholi, P.; Thant, C.; Reiter, J.; Chen, K.; Markov, V.; Taniguchi, H.; Yamaguchi, R.; Ebi, H.; Evans, J.; Jiang, J.; Lee, B.; Wildes, D.; de Stanchina, E.; Smith, J. A. M.; Singh, M.; Rosen, N. |
| Article Title: | Combined inhibition of KRAS(G12C) and mTORC1 kinase is synergistic in non-small cell lung cancer |
| 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. © The Author(s) 2024. |
| Keywords: | signal transduction; genetics; drug potentiation; mouse; animal; metabolism; animals; mice; protein kinase inhibitor; carcinoma, non-small-cell lung; lung neoplasms; bim protein; drug effect; drug screening; pathology; xenograft model antitumor assays; enzyme activity; cell line, tumor; inhibitor; drug synergism; protein kinase inhibitors; lung tumor; protein mcl 1; tumor cell line; drug therapy; cyclin d1; protein p21; proto-oncogene proteins p21(ras); kras protein, human; non small cell lung cancer; inhibition; cell; bcl-2-like protein 11; mammalian target of rapamycin complex 1; tor serine-threonine kinases; target of rapamycin kinase; myeloid cell leukemia sequence 1 protein; cancer; humans; human; female; induced response; mechanistic target of rapamycin complex 1 |
| Journal Title: | Nature Communications |
| Volume: | 15 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-07-19 |
| Start Page: | 6076 |
| Language: | English |
| DOI: | 10.1038/s41467-024-50063-z |
| PUBMED: | 39025835 |
| PROVIDER: | scopus |
| PMCID: | PMC11258147 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Neal Rosen -- Source: Scopus |
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