2. Academic Validation
  3. Mitochondrial metabolic rewiring sensitizes mTORC1 inhibitor persister cells to cuproptosis

Mitochondrial metabolic rewiring sensitizes mTORC1 inhibitor persister cells to cuproptosis

  • JCI Insight. 2025 Nov 24;10(22):e187448. doi: 10.1172/jci.insight.187448.
Heng Du 1 2 3,  Heng-Jia Liu 3 4 5,  Magdalena Losko 3,  Yu Chi Yang 6,  Min Yuan 7,  Elizabeth P Henske 3,  John M Asara 7 8,  Mallika Singh 6,  David J Kwiatkowski 3
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery and.
  • 2 Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
  • 3 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  • 4 Centre for Infection Immunity and Cancer, Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Zhejiang University, Haining, Zhejiang, China.
  • 5 Edinburgh Medical School: Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom.
  • 6 Department of Biology, Revolution Medicines Inc., Redwood City, California, USA.
  • 7 Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
  • 8 Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
PMID: 41277553 DOI: 10.1172/jci.insight.187448
Abstract

Therapeutics blocking PI3K/mTOR complex 1 (mTORC1) are commonly used for tumor treatment, and at times achieve major responses, yet minimal residual disease (MRD) persists, leading to tumor relapse. We developed multiple MRD models both in vitro (rapamycin persistent, RP) and in vivo after mTORC1 inhibition. All 11 RP/MRD cell lines showed complete growth and signaling insensitivity to rapamycin but variable sensitivity to bi-steric mTORC1 inhibitors, with MtorS2035 mutations identified in 4 of 7 RP cell lines. Multiomic analyses identified a pronounced shift toward Oxidative Phosphorylation and away from glycolysis with increased mitochondrial number in all RP/MRD models. MYC and SWI/SNF expression was significantly enhanced. Both the SWI/SNF inhibitor AU-15330 and the mitochondrial complex I Oxidative Phosphorylation Inhibitor IACS-010759 showed pronounced synergy with bi-steric mTORC1 inhibitors to cause cuproptotic cell death in RP/MRD cells, suggesting these combinations as a potential patient treatment strategy for rapalog resistance.

Keywords

Cancer; Epigenetics; Metabolism; Mitochondria; Oncology.

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