Fatty Acid Synthase (FASN) as a targeted therapeutic in acquired 5-fluorouracil resistance in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies. The absence of early symptoms means that most patients are diagnosed at late stages with advanced disease. Despite progress in treatment, the overall prognosis remains poor mainly due to their inherent and/or acquired resistance to conventional therapies. The efficacy of new treatment strategies has been hampered by the lack of efficient preclinical models recapitulating the heterogeneity and complexity of this cancer resulting in the ineffective clinical translation of novel targeted therapeutic options. Acquired drug resistance to 5-fluorouracil (5-FU) (the backbone chemotherapeutic of treatment regimens for PDAC) in two patient-derived organoids (PDOs) were developed to investigate the mechanisms of chemotherapeutic resistance and identify novel targeted therapeutic strategies. Proteomic and pathway analyses identified Fatty Acid Synthase (FAS/FASN) as a key dysregulated protein with therapeutic vulnerabilities. Targeting FASN as a modulator of 5-FU resistance, via pharmacological inhibitor and phototoxic peptide conjugate, resensitised cells to 5-FU in acquired organoid models of resistance. PDOs are valuable tools for modelling drug resistance and offer opportunities to discover novel therapeutic approaches to circumvent the emergence of drug resistance.