Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer.

ABSTRACT: Resistance to mitochondrial apoptosis is a major driver of chemoresistance in pancreatic ductal adenocarcinoma (PDAC). However, pharmacological manipulation of the mitochondrial apoptosis threshold in PDAC cells remains an unmet therapeutic goal. We hypothesized that fatty acid synthase inhibitors (FASNis), a family of targeted metabolic therapeutics recently entering the clinic, could lower the apoptotic threshold in chemoresistant PDAC cells and be synergistic with BH3 mimetics that neutralize anti-apoptotic proteins. Computational studies with TVB-3166 and TVB-3664, two analogues of the clinical-grade FASNi TVB-2640 (denifanstat), confirmed their uncompetitive behavior towards NADPH when bound to the FASN ketoacyl reductase domain. The extent of NADPH accumulation, a consequence of FASN

SUBMITTER: Steen TV 

PROVIDER: S-EPMC11908614 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature