Poly (ADP-Ribose) Polymerase (PARP), an Emerging Target for Controlling Metastatic Prostate Cancer under BRCAness

Abstract

PARP1 is identified as an enzyme for addition of poly (ADP-ribose) to target protein(s) and is also important for DNA repair at the site of DNA single strand break (SSB). However, under PARP-inactivated states, unrepaired SSB is converted to double strand break (DSB) in S-phase, and then homologous recombination (HR) system participates in repair of DSB-injured DNA. In this process, BRCA1/2 and their binding effectors, such as RAD51 and PALB1, are recruited to the injured site for initiating HR-based DNA repair. If HR-associated molecules, such as BRCA1/2, are deficient via a dysfunctional mutation or down-regulated (so called, BRCAness), cancer cells undergo further DSBs and eventually result in apoptotic cell death. In response to HR-deficiency, PARP1 is activated to repress SSB, a source of DSB before DNA replication, hence suggesting a new target of PARP1 for inducing synthetic lethality under BRCAness. Indeed, PARP1 inhibitor (PARPi) is found to be useful for delaying the progression of BRCA1/2-mutated ovarian cancers in phase-II clinical trials. Metastatic prostate cancer (PCa) is now the second leading cause of cancer deaths among males in the Western countries. Radiation and androgen receptor inhibition (ARi) (i.e., pharmaceutical castration) are the standard therapy to delay PCa progression, but these conventional treatments result in a malignant selection of castration-resistant PCa clones. Previous studies described the potential use of PARPi for sensitizing radiotherapy or chemotherapy to castration-sensitive PCa in a rodent model. The recent highlighted finding is that ARi treatment down-regulates BRCA1, Rad51, Rad54 and RMI2, all are necessary for HR post-DNA DSB damage, thus indicating the acquisition of BRCAness-like phenotypes by ARi. In this review, we will describe the recent information on significance of PARPi in advanced PCa. Clinical effects are now being evaluated in patients with metastatic PCa, and some are promising. PARP1 inhibition may become a principle-based strategy for arresting metastatic PCa, if patient selection is carefully performed, on the basis of genomic (or phenotypic) detection of BRCAness.