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.

An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer

“…On the other hand, during treatment induced tumor evolution, DDR sufficient cancer cells can outgrow the DDR deficient tumor clones, thus leading to the development of treatment resistance. MRN complex (MRE11, RAD50 and NBN) is the initial core of DNA double-strand breaks (DSB) repair machinery, while PALB2, RAD51 among several other key regulators contribute to the later stages of DDR [47] . Our study identifies the enrichment of several key regulators of DDR in m6Ascore-high tumors, indicating a potential link between m6A, DDR, and immune evasion in PDAC.…”

Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer

“…12 However, BRCA1 or BRCA2 are not the most frequently mutated DDR genes in sporadic PDAC in a general Western population. ATM is mutated in up to 5% of sporadic PDAC 13 and operates as a key enzyme in homologous recombination (HR) repair, mounting a bona fide HR-defective (HRDness) 14 model for PDAC. 15 Our group previously showed that ATM deficiency, even on heterozygous deletion, causes metastatic and aggressive PDAC undergoing epithelial-mesenchymal transition (EMT), negatively impacting prognosis in humans and mice.…”

LncRNA SNHG17 Promotes Tumor Progression and Predicts Poor Survival in Human Renal Cell Carcinoma via Sponging miR-328-3p

“…[25,27,28] Moreover, H2AX had been proved to be involved in cancer initiation and progression. [29,30] Also, H2AX plays a vital role in regulating tumor cell proliferation [31] and angiogenesis. [32]…”