An update on PARP inhibitors for the treatment of cancer

Abstract

The development of poly (adenosine diphosphate [ADP]) ribose polymerase (PARP) inhibitors (PARPi) has progressed greatly over the last few years and has shown encouraging results in the BRCA1/2 mutation-related cancers. This article attempts to summarize the rationale and theory behind PARPi, the clinical trials already reported, as well as ongoing studies designed to determine the role of PARPi in patients with and without germline mutations of BRCA genes. Future plans for PARPi both as monotherapy and in combination with standard cytotoxics, other biological agents, and as radiosensitizers are also covered. The widening scope of PARPi adds another important targeted agent to the growing list of molecular inhibitors; future and ongoing trials will identify the most effective role for PARPi, including for patients other than BRCA germline mutation carriers.

Keywords: BRCA genes; BRCA germline mutation carriers; PARPi; cytotoxics; germline mutations; radiosensitizers.

Figure 1

(A) DNA repair pathways; (B) PARP senses DNA SSBs and utilizes NAD⁺ as a substrate to form PAR, which attach to a range of target proteins including PARP-1 itself and BER proteins. This posttranslational modification is termed PARylation. Notes: (A) There are six DNA repair pathways, two for repair of DNA DSBs and four for repair of SSBs. PARP is known to be involved in BER and has been shown to be a negative regulator of NHEJ (low-fidelity, error-prone pathway). PARP inhibition therefore leads to disruption of BER and in HR-deficient cells, increased reliance on error-prone NHEJ. Abbreviations: BER, base excision repair; DSBs, double-strand DNA breaks; HR, homologous recombination; NAD⁺, nicotinamide adenine dinucleotide; NHEJ, nonhomologous end joining; PAR, polymers of ADP-ribose; PARP, poly (adenosine diphosphate [ADP]) ribose polymerase; SSBs, single-strand DNA breaks.

Figure 2

BRCA-deficient cells are highly reliant on BER as well as SSA and the error prone NHEJ pathway for DNA repair, both of which are influenced by PARPi. Abbreviations: BER, base excision repair; DSB, double-strand DNA breaks; HR, homologous recombination; NHEJ, nonhomologous end joining; SSA, single-strand annealing; SSBs, single-strand DNA breaks; PARPi - poly (adenosine diphosphate [ADP]) ribose polymerase inhibitors.

Figure 3

PARP inhibitor – mechanism of action. Notes: (A) PARP attaches to site(s) of DNA damage and is unable to dissociate due to inhibition of PARP autoPARylation causing PARP trapping and cytotoxic PARP–DNA complexes. The degree of ‘PARP trapping’ appears to vary between the different inhibitors currently under investigation and may explain the differences in toxicity profile observed, with olaparib and niraparib having greater potency compared to veliparib. (B) SSBs accumulate, leading to DSBs, which are unrepaired in cells deficient in HR proteins, ultimately leading to cell death. Abbreviations: DSBs, double-strand DNA breaks; HR, homologous recombination; PARP, poly (adenosine diphosphate [ADP]) ribose polymerase; SSBs, single-strand DNA breaks.

Figure 4

Schema of development of first PARPi, olaparib (AZD2281). Abbreviations: HR, homologous recombination; PARP, poly (adenosine diphosphate [ADP]) ribose polymerase; PARPi, PARP inhibitor.