Inhibition of poly (ADP-Ribose) polymerase: A promising strategy targeting pancreatic cancer with BRCAness phenotype

Abstract

The use of chemotherapeutic regimens for the treatment of pancreatic cancer is still limited because pancreatic cancer is usually diagnosed at an advanced stage as a refractory disease in which symptoms are difficult to recognize in the early stages. Furthermore, at advanced stages, there are important challenges to achieve clinical benefit and symptom resolution, even with the use of an expanded spectrum of anticancer drugs. Recently, a point of reduced susceptibility to conventional chemotherapies by breast cancer susceptibility gene (BRCA) mutations led to a new perspective for overcoming the resistance of pancreatic cancer within the framework of increased genome instability. Poly (ADP-Ribose) polymerase (PARP) -1 is an enzyme that can regulate intrinsic functions, such as response to DNA damage. Therefore, in an environment where germline mutations in BRCAs (BRCAness) inhibit homologous recombination in DNA damage, resulting in a lack of DNA damage response, a key role of PARP-1 for the adaptation of the genome instability could be further emphasized. Here, we summarized the key functional role of PARP-1 in genomic instability of pancreatic cancer with the BRCAness phenotype and listed clinical applications and outcomes of PARP-1 inhibitors to highlight the importance of targeting PARP-1 activity.

Keywords: Pancreatic cancer; BRCAness; Poly (ADP-Ribose) polymerase-1; PARylation; Poly (ADP-Ribose) polymerase-1 inhibitor

Core Tip: The incidence of germline mutations of the breast cancer susceptibility gene (BRCA), defined as BRCAness, that can be targeted for pancreatic cancer is 9%-17%. Mutations in BRCAs are responsible for causing genetic instability and worsening the prognosis. Therefore, inhibition of poly (ADP-Ribose) polymerase-1 has emerged as a promising therapeutic target for BRCAness pancreatic cancer within the framework of an increase in genome instability.