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

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.

Chemoresistance to additive PARP/PI3K dual inhibition in triple-negative breast cancer cell lines is associated with adaptive stem cell-like prevalence

“…3c) exhibited an overall lower sensitivity to both agents and, similar to a BT-20 trend, only PI3Ki for 24 hr, with PARPi added for 48 hr, reduced cell viability more than 10% over OB: 56.8% viability vs. 69.5% respectively (not significant). Indeed, initial PI3K inhibition may have re-established “BRCAness” in this BRCA1 -mutated cell line (Abbotts, Dellomo, & Rassool, 2022). In MDA-MB-231 cells (Fig.…”

Targeting Homologous Recombination Deficiency in Ovarian Cancer with PARP Inhibitors: Synthetic Lethal Strategies That Impact Overall Survival

“…The 17-member PARP family of enzymes includes PARP1, PARP2, PARP3, PARP4 (also known as Vault PARP) and tankyrases 1 and 2 (PARP5a and PARP5b) [40][41][42]. PARPs are involved in many key cellular processes including regulating transcription, translation, telomere maintenance, remodelling the chromatin landscape and, importantly in the context of this review, DNA repair [43,44]. PARPs catalyse the transfer of poly (ADP-ribose) (poly(adenosinediphosphate-ribose)) to target proteins.…”

Harnessing the cooperation between DNA‐PK and cGAS in cancer therapies

“…Indeed, PARP1 inhibitors can induce tumour cell death in cancers presenting loss of function mutations in BReast CAncer 1 and 2 genes (BRCA1/2), characterised by HR defects. [88,89] They have also been shown to increase cancer sensitivity to irradiation when combined to DNA-PKcs inhibitors. [90] In addition, PARP1 inhibition increases tumour immunogenicity via the cGAS-STING pathway, [91,92] which may be explained by the interaction between PARP1 and cGAS [81] (Figure 2).…”