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

Nat Commun. 2024 Jul 19;15(1):6076. doi: 10.1038/s41467-024-50063-z.

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.

MeSH terms

  • Animals
  • Bcl-2-Like Protein 11 / genetics
  • Bcl-2-Like Protein 11 / metabolism
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Line, Tumor
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Drug Synergism*
  • Female
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Mechanistic Target of Rapamycin Complex 1* / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1* / metabolism
  • Mice
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins p21(ras)* / genetics
  • Proto-Oncogene Proteins p21(ras)* / metabolism
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins p21(ras)
  • KRAS protein, human
  • TOR Serine-Threonine Kinases
  • Protein Kinase Inhibitors
  • Cyclin D1
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Bcl-2-Like Protein 11