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Bromo- and Extra-Terminal Domain Inhibitors Induce Mitochondrial Stress in Pancreatic Ductal Adenocarcinoma.
Rana, Manjul; Kansal, Rita G; Bisunke, Bijay; Fang, Jie; Shibata, David; Bajwa, Amandeep; Yang, Jun; Glazer, Evan S.
Afiliación
  • Rana M; Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
  • Kansal RG; Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
  • Bisunke B; Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
  • Fang J; Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
  • Shibata D; St. Jude Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Bajwa A; Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
  • Yang J; Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
  • Glazer ES; Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
Mol Cancer Ther ; 22(8): 936-946, 2023 08 01.
Article en En | MEDLINE | ID: mdl-37294884
ABSTRACT
Identifying novel, unique, and personalized molecular targets for patients with pancreatic ductal adenocarcinoma (PDAC) remains the greatest challenge in altering the biology of fatal tumors. Bromo- and extra-terminal domain (BET) proteins are activated in a noncanonical fashion by TGFß, a ubiquitous cytokine in the PDAC tumor microenvironment (TME). We hypothesized that BET inhibitors (BETi) represent a new class of drugs that attack PDAC tumors via a novel mechanism. Using a combination of patient and syngeneic murine models, we investigated the effects of the BETi drug BMS-986158 on cellular proliferation, organoid growth, cell-cycle progression, and mitochondrial metabolic disruption. These were investigated independently and in combination with standard cytotoxic chemotherapy (gemcitabine + paclitaxel [GemPTX]). BMS-986158 reduced cell viability and proliferation across multiple PDAC cell lines in a dose-dependent manner, even more so in combination with cytotoxic chemotherapy (P < 0.0001). We found that BMS-986158 reduced both human and murine PDAC organoid growth (P < 0.001), with associated perturbations in the cell cycle leading to cell-cycle arrest. BMS-986158 disrupts normal cancer-dependent mitochondrial function, leading to aberrant mitochondrial metabolism and stress via dysfunctional cellular respiration, proton leakage, and ATP production. We demonstrated mechanistic and functional data that BETi induces metabolic mitochondrial dysfunction, abrogating PDAC progression and proliferation, alone and in combination with systemic cytotoxic chemotherapies. This novel approach improves the therapeutic window in patients with PDAC and offers another treatment approach distinct from cytotoxic chemotherapy that targets cancer cell bioenergetics.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2023 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2023 Tipo del documento: Article