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Bromo- and Extra-Terminal Domain Inhibitors Induce Mitochondrial Stress in Pancreatic Ductal Adenocarcinoma

Manjul Rana1, Rita G Kansal1, Bijay Bisunke1,2

  • 1Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.

Molecular Cancer Therapeutics
|June 9, 2023
PubMed

Insights

Bromo- and extra-terminal domain (BET) inhibitors disrupt pancreatic ductal adenocarcinoma (PDAC) cell growth and mitochondrial metabolism. This novel approach shows promise alone and with chemotherapy, targeting cancer cell bioenergetics.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) presents a significant challenge due to the lack of unique molecular targets.
  • Transforming growth factor beta (TGFβ) activates Bromo- and extra-terminal domain (BET) proteins within the PDAC tumor microenvironment.
  • BET inhibitors (BETi) are emerging as a potential therapeutic strategy targeting PDAC through novel mechanisms.

Purpose of the Study:

  • To investigate the efficacy of the BET inhibitor BMS-986158 in preclinical models of pancreatic ductal adenocarcinoma.
  • To evaluate the effects of BMS-986158 on cellular proliferation, organoid growth, cell-cycle progression, and mitochondrial metabolism.
  • To assess the combination therapy of BMS-986158 with standard cytotoxic chemotherapy (gemcitabine + paclitaxel [GemPTX]).

Main Methods:

  • Utilized patient-derived and syngeneic murine models of PDAC.
  • Assessed cell viability, proliferation, and organoid growth in response to BMS-986158.
  • Analyzed cell-cycle progression and mitochondrial metabolic function, including respiration and ATP production.
  • Compared the effects of BMS-986158 alone and in combination with GemPTX.

Main Results:

  • BMS-986158 significantly reduced PDAC cell viability and proliferation in a dose-dependent manner.
  • The combination of BMS-986158 with GemPTX demonstrated enhanced efficacy (P < 0.0001).
  • BMS-986158 induced cell-cycle arrest and disrupted mitochondrial metabolism, impairing cellular respiration and ATP production in PDAC models (P < 0.001).

Conclusions:

  • BET inhibitors, such as BMS-986158, represent a novel therapeutic class for PDAC by targeting cancer cell bioenergetics.
  • BMS-986158 effectively abrogates PDAC progression and proliferation through mitochondrial metabolic disruption.
  • This approach offers a distinct therapeutic strategy beyond cytotoxic chemotherapy, potentially improving the therapeutic window for PDAC patients.

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