Overcoming therapeutic resistance in pancreatic cancer: Emerging opportunities by targeting BRCAs and p53.

Pancreatic cancer (PC) is characterized by (epi)genetic and microenvironmental alterations that negatively impact the treatment outcomes. New targeted therapies have been pursued to counteract the therapeutic resistance in PC. Aiming to seek for new therapeutic options for PC, several attempts have been undertaken to exploit BRCA1/2 and TP53 deficiencies as promising actionable targets. The elucidation of the pathogenesis of PC highlighted the high prevalence of p53 mutations and their connection with the aggressiveness and therapeutic resistance of PC. Additionally, PC is associated with dysfunctions in several DNA repair-related genes, including BRCA1/2, which sensitize tumours to DNA-damaging agents. In this context, poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) were approved for mutant BRCA1/2 PC patients. However, acquired drug resistance has become a major drawback of PARPi. This review emphasizes the importance of targeting defective BRCAs and p53 pathways for advancing personalized PC therapy, with particular focus on how this approach may provide an opportunity to tackle PC resistance.