Prostate cancer and PARP inhibitors: progress and challenges

Abstract

Despite survival improvements achieved over the last two decades, prostate cancer remains lethal at the metastatic castration-resistant stage (mCRPC) and new therapeutic approaches are needed. Germinal and/or somatic alterations of DNA-damage response pathway genes are found in a substantial number of patients with advanced prostate cancers, mainly of poor prognosis. Such alterations induce a dependency for single strand break reparation through the poly(adenosine diphosphate-ribose) polymerase (PARP) system, providing the rationale to develop PARP inhibitors. In solid tumors, the first demonstration of an improvement in overall survival was provided by olaparib in patients with mCRPC harboring homologous recombination repair deficiencies. Although this represents a major milestone, a number of issues relating to PARP inhibitors remain. This timely review synthesizes and discusses the rationale and development of PARP inhibitors, biomarker-based approaches associated and the future challenges related to their prescription as well as patient pathways.

Keywords: DNA repair; Homologous recombination repair; PARP inhibitors; Prostate cancers.

Fig. 1

Homologous recombination repair pathways. Double-strand breaks are detected by different proteins such as FANC complex or ATM/CHEK2. They recruit homologous stand invasion effectors, including BRCA1, BRCA2, PALB2 and RAD51, on the break site to carry out a faithful DNA repair. DSB double-strand break, HRR homologous recombination repair

Fig. 2

PARP inhibitors action mechanisms. Catalytic lethality. a PARP is recruited on single-stand breaks (SSB) and PARylates to recruit base-excision repair (BER) agents to repair SSB. b PARPi are competitive inhibitors of PARP and prevent PARylation from occurring. So, BER systems are not recruited and SSB is not repaired, allowing synthetic lethality. Trapping lethality. c Nascent DNA on replication forks is protected from nuclease action by a BRCA1/2 shield. d Inactivated PARP is locked on SSB; thus, the replication fork gets stale. In BRCA1/2 deficient cells, nucleases have the time to degrade nascent DNA, leading to cell death

Fig. 3

Principle of synthetic lethality reached with PARP inhibitors (PARPi) used in homologous recombination deficient (HRD) cells. a In standard conditions, PARP proteins repair single-stand breaks (SSB). b In homologous recombination repair (HRR)-competent cells, the use of PARPi prevents SSB from repairing. Though replication, this converts SSB into double-strand breaks (DSB), and cells survive using HRR. c In HRD cells with PARPi, neither SSB nor DSB could be repaired. This leads to cell death, through a synergy between PARPi and HRD called synthetic lethality

Fig. 4

Resistance mechanism to PARP inhibitors. Increased drug efflux. Overexpression of drug-efflux transporter genes, such as ABCB1, increases the number of drug effluxion pumps and prevents PARP inhibitors (PARPi) from reaching cell nucleus. Decreased PARP trapping. Deletion of PARP1 or mutations in its DNA-binding domains avoid trapping to occur. This confers cells with a resistance to PARPi. Alternatively, increased PARylation through loss of inhibitors, as PARG, produces the same effects with resistance to PARPi. Stabilization of stalled fork. Nucleases actions on nascent DNA are delayed or reduced by the inhibition of proteins in charge of their recruitment to the fork. Restoration of Homologous Recombination Repair (HRR). Mutational reversion or occurrence of a second mutation, which restores functional BRCA1/2 proteins, prevents the occurrence of synthetic lethality. Loss of inhibitors of HRR such as 53BP1 leads to the same resistance