Pharmacologic Induction of BRCAness in BRCA-Proficient Cancers: Expanding PARP Inhibitor Use

SIMPLE SUMMARY: BRCA1 and−2 are critical components of the homologous recombination pathway of DNA repair required to effectively repair DNA double strand breaks, leading to an increased cancer risk in patients with inherited BRCA mutations. An additional subset of cancers exhibit ‘BRCAness’, harboring repair defects stemming from mutations in non-BRCA DNA repair genes. Both BRCA-mutant cancers and cancers with a BRCAness phenotype are sensitive to PARP inhibitors, a class of cancer therapy drugs that inhibit the repair of DNA single strand breaks. To expand the use of PARP inhibitors to a larger group of patients, studies have focused on new combination strategies using agents that can induce BRCAness. This review focuses on the current status of drug-induced BRCAness in combination with PARP inhibitors to enhance cancer treatment. ABSTRACT: The poly(ADP-ribose) polymerase (PARP) family of proteins has been implicated in numerous cellular processes, including DNA repair, translation, transcription, telomere maintenance, and chromatin remodeling. Best characterized is PARP1, which plays a central role in the repair of single strand DNA damage, thus prompting the development of small molecule PARP inhibitors (PARPi) with the intent of potentiating the genotoxic effects of DNA damaging agents such as chemo- and radiotherapy. However, preclinical studies rapidly uncovered tumor-specific cytotoxicity of PARPi in a subset of cancers carrying mutations in the BReast CAncer 1 and 2 genes (BRCA1/2), which are defective in the homologous recombination (HR) DNA repair pathway, and several PARPi are now FDA-approved for single agent treatment in BRCA-mutated tumors. This phenomenon, termed synthetic lethality, has now been demonstrated in tumors harboring a number of repair gene mutations that produce a BRCA-like impairment of HR (also known as a ‘BRCAness’ phenotype). However, BRCA mutations or BRCAness is present in only a small subset of cancers, limiting PARPi therapeutic utility. Fortunately, it is now increasingly recognized that many small molecule agents, targeting a variety of molecular pathways, can induce therapeutic BRCAness as a downstream effect of activity. This review will discuss the potential for targeting a broad range of molecular pathways to therapeutically induce BRCAness and PARPi synthetic lethality.