DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives

Complex rearrangement patterns and mitotic errors are hallmarks of most pancreatic ductal adenocarcinomas (PDAC), a disease with dismal prognosis despite some therapeutic advances in recent years. DNA double-strand breaks (DSB) bear the greatest risk of provoking genomic instability, and DNA damage repair (DDR) pathways are crucial in preserving genomic integrity following a plethora of damage types. Two major repair pathways dominate DSB repair for safeguarding the genome integrity: non-homologous end joining and homologous recombination (HR). Defective HR, but also alterations in other DDR pathways, such as BRCA1, BRCA2, ATM and PALB2, occur frequently in both inherited and sporadic PDAC. Personalised treatment of pancreatic cancer is still in its infancy and predictive biomarkers are lacking. DDR deficiency might render a PDAC vulnerable to a potential new therapeutic intervention that increases the DNA damage load beyond a tolerable threshold, as for example, induced by poly (ADP-ribose) polymerase inhibitors. The Pancreas Cancer Olaparib Ongoing (POLO) trial, in which olaparib as a maintenance treatment improved progression-free survival compared with placebo after platinum-based induction chemotherapy in patients with PDAC and germline BRCA1/2 mutations, raised great hopes of a substantially improved outcome for this patient subgroup. This review summarises the relationship between DDR and PDAC, the prevalence and characteristics of DNA repair mutations and options for the clinical management of patients with PDAC and DNA repair deficiency.y

Automated summary

Complex rearrangement patterns and mitotic errors are characteristics of most PDAC, caused by DNA double-strand breaks and defective DNA repair pathways. DSB repair pathways, such as HR, play a crucial role in maintaining genomic integrity, and deficiencies in DDR pathways like BRCA1 and BRCA2 are common in both inherited and sporadic PDAC, leading to potential vulnerabilities to new therapeutic interventions. The POLO trial with olaparib showed promising results in PDAC patients with germline BRCA1/2 mutations, suggesting a potential for improved outcomes in this subgroup.