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

Juliana Calheiros; Vincenzo Corbo; Lucília Saraiva

doi:10.1016/j.bbcan.2023.188914

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

Biochim Biophys Acta Rev Cancer. 2023 Jul;1878(4):188914. doi: 10.1016/j.bbcan.2023.188914. Epub 2023 May 16.

Authors

Juliana Calheiros¹, Vincenzo Corbo², Lucília Saraiva³

Affiliations

¹ LAQV/REQUIMTE, Laboratόrio de Microbiologia, Departamento de Ciências Biolόgicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal.
² Department of Engineering for Innovation Medicine (DIMI), University and Hospital Trust of Verona, Verona, Italy; ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy.
³ LAQV/REQUIMTE, Laboratόrio de Microbiologia, Departamento de Ciências Biolόgicas, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal. Electronic address: lucilia.saraiva@ff.up.pt.

PMID: 37201730
DOI: 10.1016/j.bbcan.2023.188914

Abstract

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.

Keywords: BRCA1/2; Drug resistance; Pancreatic cancer; Targeted therapy; p53.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

BRCA1 Protein* / genetics
BRCA2 Protein / genetics
Drug Resistance, Neoplasm / genetics
Humans
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / genetics
Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
Poly(ADP-ribose) Polymerases / genetics
Poly(ADP-ribose) Polymerases / metabolism
Tumor Suppressor Protein p53 / genetics

Substances

BRCA1 Protein
BRCA1 protein, human
BRCA2 Protein
BRCA2 protein, human
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases
Tumor Suppressor Protein p53
TP53 protein, human