Recent advancements in PARP inhibitors-based targeted cancer therapy

Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPi) are a new class of agents with unparalleled clinical achievement for driving synthetic lethality in BRCA-deficient cancers. Recent FDA approval of PARPi has motivated clinical trials centered around the optimization of PARPi-associated therapies in a variety of BRCA-deficient cancers. This review highlights recent advancements in understanding the molecular mechanisms of PARP 'trapping' and synthetic lethality. Particular attention is placed on the potential extension of PARPi therapies from BRCA-deficient patients to populations with other homologous recombination-deficient backgrounds, and common characteristics of PARPi and non-homologous end-joining have been elucidated. The synergistic antitumor effect of combining PARPi with various immune checkpoint blockades has been explored to evaluate the potential of combination therapy in attaining greater therapeutic outcome. This has shed light onto the differing classifications of PARPi as well as the factors that result in altered PARPi activity. Lastly, acquired chemoresistance is a crucial issue for clinical application of PARPi. The molecular mechanisms underlying PARPi resistance and potential overcoming strategies are discussed.

Keywords: BRCA1/2; PARP1; acquired chemoresistance to PARP inhibitors; classifications of PARP inhibitors; immunotherapy; synthetic lethality.

Figure 1.

Schematic representation of the mechanisms contributing to PARP inhibitors (PARPi)-resistance and potential overcoming strategies. Homologous recombination (HR) restoration, replication fork protection and PARP1 mutations are three categories of mechanisms underlying acquired PARPi-resistance. HR restoration is usually induced by in-frame secondary mutations restoring BRCA1/2 function, upregulation of the remaining functional allele, loss of BRCA1 promoter methylation, and loss of 53BP1, ARID1A or GPBP1, and can be overcome via combining PARPi with a series of inhibitors that can result in chemical HRDness. Replication fork protection is mediated by loss of PTIP or EZH2 that impairs the recruitment of the MRE11 or MUS81 nuclease to stalled replication forks, and upregulation of the ATR/CHK1 pathway that can be potentially resolved via combining PARPi with inhibitors of ATR, ATM or CHK1. Mutations in PARP1 that can affect interdomain contacts, DNA binding potency or inhibitor binding also have a potential to lead to PARPi-resistance, which might have to be resolved by developing new inhibitors.