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

Abstract

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.

Keywords: DNA damage; chemotherapy; pancreatic cancer.

Figure 1

Overview of main DNA lesions and their related DNA damage repair pathways. Schematic representation of I. single-strand break repair by direct and indirect base excision repair, II. double-strand break repair by homologous recombination and non-homologous end joining, III. replication error repair by mismatch repair and IV. DNA adducts repair by either transcription-coupled nucleotide excision repair (TC-NER) or global genomic nucleotide excision repair (GG-NER). Symbolic pills show potential targeted therapeutic interventions by PARP inhibition and platinum agents (Pt). Black stars represent an indirect single-strand break. Dashed circles emphasize proteins found to be mutated in human pancreatic ductal adenocarcinoma. Dashed lines represent the regulatory role of ATM and ATR on non-homologous end joining. alt-NHEJ, alternative non-homologous end joining; BER, base excision repair; c-NHEJ, canonical non-homologous end joining; MMR, mismatch repair; ROS, reactive oxygen species; SSB, single-strand break.

Figure 2

Frequency of gene alterations in primary pancreatic ductal adenocarcinomas. Three available pancreatic cancer sequencing data sets (n=751) were assessed for somatic gene mutations (panel of 118 genes from and additionally extended in more detail for DNA damage repair genes from cBioPortal). DDR, DNA damage repair.

Figure 3

Schematic representation of pancreatic cancer progression in a homologous recombination-deficient context. HRDness resulting from ATM deficiency sensitises pancreatic cells to exogenous and endogenous DNA damaging factors enabling an oncogenic cascade through acinar-to-ductal metaplasia. Sustained impaired double-strand break repair results in accelerated genomic instability driving the progression of preneoplastic PanIN stages to HRD pancreatic ductal adenocarcinoma (PDAC). Persistent HRD or therapeutically induced HRD by eg, ATMi renders cancer cells vulnerable to therapeutic interventions promoting DNA damage. Monotherapeutic approaches as PARPi subsequently tend to complex multidrug resistance (MDR) involving epithelial-to-mesenchymal-transition (EMT) and alternative DNA repair. Smart tailored use of synergistically druggable vulnerabilities within the DNA damage repair machinery could be exploited to hit HRD tumors “hard and early” and prevent further MDR acquisition, as eg, recently shown upon inhibition of PARP, ATR and DNA-PKcs. ADM, acinar-to-ductal metaplasia; ADR, acinar-to-ductal reprogramming; DSB, double-strand break; HRD, homologous recombination-deficient; NHEJ, non-homologous end joining; PanIN, pancreatic intraepithelial neoplasia.