PARP Inhibitors: Clinical Limitations and Recent Attempts to Overcome Them

Abstract

PARP inhibitors are the first clinically approved drugs that were developed based on synthetic lethality. PARP inhibitors have shown promising outcomes since their clinical applications and have recently been approved as maintenance treatment for cancer patients with BRCA mutations. PARP inhibitors also exhibit positive results even in patients without homologous recombination (HR) deficiency. Therapeutic effects were successfully achieved; however, the development of resistance was unavoidable. Approximately 40–70% of patients are likely to develop resistance. Here, we describe the mechanisms of action of PARP inhibitors, the causes of resistance, and the various efforts to overcome resistance. Particularly, we determined the survival probability of cancer patients according to the expression patterns of genes associated with HR restoration, which are critical for the development of PARP inhibitor resistance. Furthermore, we discuss the innovative attempts to degrade PARP proteins by chemically modifying PARP inhibitors. These efforts would enhance the efficacy of PARP inhibitors or expand the scope of their usage.