Selective PARP-2 targeted therapy as a new strategy in pancreatic cancer: Beyond personalized medicine

Abstract

Pancreatic ductal adenocarcinoma (PDA) has been predicted to soon become the second leading cause of cancer related deaths. Although poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have emerged as promising anti-cancer drugs for BRCA mutated tumors, in pancreatic cancer, phase III clinical results have failed. Major limitations of PARPi are due to their lack of selectivity. In this regard, we have recently demonstrated that Parp-2, but not Parp-1, plays a specific role in replicative stress, which is a known PDA hallmark. Therefore, we hypothesized that Parp-2 may represent a new potential target to fight against PDA. Importantly, Parp-2 genetic deletion in Ela-myc transgenic mice resulted in a 43% increase in animal survival. Tumor histopathological characterization showed that Parp-2 inhibition hampers acinar-to- ductal metaplasia, a key event in pancreatic cancer initiation. Parp-2 loss in vitro significantly decreased tumoroid generation capacity and induced DNA damage accumulation, increasing replicative stress and apoptosis. Molecular analysis of Ela-myc:Parp-2-/- vs Ela-myc Parp- 2+/+ pancreatic tumors in preneoplastic lesions, indicated that Parp-2 inhibition resulted in a less immune-evasive environment. Moreover, GSEA at late tumor stages shows p53 pathway enrichment in Ela-myc Parp-2+/+ vs Ela-myc:Parp-2-/-. Indeed, p53 inactivation was found in primary cell lines established from late stage Ela-myc:Parp-2-/- tumors, suggesting that loss of function of this pathway is required for tumor progression in the absence of Parp-2. Altogether our data highlight that Parp-2 is a novel target in pancreatic cancer and open new avenues for therapeutic intervention against this aggressive tumor by using specific Parp-2 pharmacological inhibitors.