Reprogramming oncogenic mitochondria in pancreatic adenocarcinoma through BRD4 inhibition leads to programmed cell death

Pancreatic ductal adenocarcinoma (PDA) is an almost universally fatal disease. Recent advances in the understanding of PDA bioenergetic dynamic equilibrium have illuminated a potential therapeutic target in bromodomain-related protein 4 (BRD4), the most active member of the bromo- and extraterminal domain (BET) protein family of transcription factors. We previously demonstrated that BET inhibitors (BETi) decrease PDA cell proliferation and enhance chemosensitivity. We hypothesized that BETi activates Mitophagy and Ferroptosis in PDA. Using pharmacological and genetic BRD4 inhibition in PDA patient-derived models, we investigated the effects of BETi on mitochondrial function, mitochondrial protein complex production, ATP production, cellular respiration, Autophagy/Mitophagy, and murine tumor growth with BMS-986158, a BETi. We determined the role of BRD4 in PDA by evaluating Mitophagy and Autophagy. In PDA models, we found that BETi decreased cellular respiration (P < .01), decreased ATP production (P < .001), and increased intracellular iron uptake (P < .01) while inducing Mitophagy through dysregulated mitochondria complex protein levels. Murine PDA tumors grew slower and were smaller when treated with BETi compared with the control treatment. PDA tumors from experimentally treated mice contained more lipid vacuoles than those from the vehicle control group (P < .01), consistent with Ferroptosis. BETi therapy decreased isocitrate dehydrogenase-1 expression, indicating increased chemosensitivity. BETi dysregulate mitochondrial complexes inducing Mitophagy. BETi is a promising therapeutic strategy for attacking oncogenic mitochondrial behavior in PDA. We demonstrated a series of mitochondrial-centered events in a temporal sequence leading to cell death. This treatment controls tumors and increases chemosensitivity, offering a novel therapeutic strategy. SIGNIFICANCE STATEMENT: Bromo- and extraterminal domain inhibition is a novel therapeutic strategy for attacking oncogenic mitochondrial behavior in pancreatic ductal adenocarcinoma. Using this strategy in patient-derived models, this study demonstrated a series of mitochondrial-centered events in a temporal sequence leading to cell death and tumor control.

Bromo- and extraterminal domain; Cancer therapeutics; Mitochondrial stress; Mitophagy; Pancreatic ductal adenocarcinoma.