American Association for Cancer Research
Browse
mct-23-0149_figure_s2_suppsf2.pdf (3.07 MB)

Figure S2 from Bromo- and Extra-Terminal Domain Inhibitors Induce Mitochondrial Stress in Pancreatic Ductal Adenocarcinoma

Download (3.07 MB)
journal contribution
posted on 2023-08-01, 08:20 authored by Manjul Rana, Rita G. Kansal, Bijay Bisunke, Jie Fang, David Shibata, Amandeep Bajwa, Jun Yang, Evan S. Glazer

Figure s2

Funding

Health Science Center, University of Tennessee (University of Tennessee Health Science Center)

HHS-NIH-NCI

Office of the Chief Mental Health Nurse-NIH-NCI

History

ARTICLE 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 TGFβ, 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.

Usage metrics

    Molecular Cancer Therapeutics

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC