Beyond Breast and Ovarian Cancers: PARP Inhibitors for BRCA Mutation-Associated and BRCA-Like Solid Tumors

Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown clinical activity in patients with germline BRCA1/2 mutation (gBRCAm)-associated breast and ovarian cancers. Accumulating evidence suggests that PARPi may have a wider application in the treatment of cancers defective in DNA damage repair pathways, such as prostate, lung, endometrial, and pancreatic cancers. Several PARPi are currently in phase I/II clinical investigation, as single-agents and/or combination therapy in these solid tumors. Understanding more about the molecular abnormalities involved in BRCA-like phenotype in solid tumors beyond breast and ovarian cancers, exploring novel therapeutic trial strategies and drug combinations, and defining potential predictive biomarkers are critical to expanding the scope of PARPi therapy. This will improve clinical outcome in advanced solid tumors. Here, we briefly review the preclinical data and clinical development of PARPi, and discuss its future development in solid tumors beyond gBRCAm-associated breast and ovarian cancers.

Keywords: BRCA mutation; BRCA-like; DNA damage repair pathway; poly(ADP-ribose) polymerase inhibitors; solid tumors.

Figure 1

PARP1 binds to DNA single strand break and catalyzes poly(ADP-ribosyl)ation of itself and acceptor proteins, which facilitates recruitment of DNA repair proteins. In addition to its reported role in base excision repair, PARP1 plays a role in activating ATM necessary for homologous recombination and inactivating DNA-dependent protein kinase, a key component of non-homologous end-joining. PARP inhibitors directly interfere with the above functions of PARP1. In addition, PARP inhibitors have been shown to trap PARP1 on damaged DNA, leading to replication and transcription fork blockage and subsequent double-strand DNA breakage. Repair of intra/interstrand crosslinks through nucleotide excision repair or homologous recombination are also important components of the DNA repair system, and whether defects in these repair pathways can confer sensitivity to PARPi are under investigation. PARP, poly(ADP-ribose) polymerase; PARPi, PARP inhibitor; DNA polβ/δ/ε, DNA polymerase beta/delta/epsilon; XRCC1, X-ray repair cross-complementing protein 1; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; KU 70/80, a.k.a XRCC6/5 (X-ray repair cross-complementing protein 6/5); ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related; γ-H2A.X, gamma-histone H2A member X; RAD51, RAD51 homolog (S. cerevisiae); ERCC1, DNA excision repair protein ERCC1; XPF, DNA repair endonclease XPF (xeroderma pigmentosum group F-complementing protein); FANC, Fanconi anemia.