PARP inhibitors: its role in treatment of cancer

Abstract

PARP is an important protein in DNA repair pathways especially the base excision repair (BER). BER is involved in DNA repair of single strand breaks (SSBs). If BER is impaired, inhibiting poly(ADP-ribose) polymerase (PARP), SSBs accumulate and become double stand breaks (DSBs). The cells with increasing number of DSBs become more dependent on other repair pathways, mainly the homologous recombination (HR) and the nonhomologous end joining. Patients with defective HR, like BRCA-deficient cell lines, are even more susceptible to impairment of the BER pathway. Inhibitors of PARP preferentially kill cancer cells in BRCA-mutation cancer cell lines over normal cells. Also, PARP inhibitors increase cytotoxicity by inhibiting repair in the presence of chemotherapies that induces SSBs. These two principles have been tested clinically. Over the last few years, excitement over this class of agents has escalated due to reported activity as single agent in BRCA1- or BRCA2-associated ovarian or breast cancers, and in combination with chemotherapy in triple negative breast cancer. This review covers the current results of clinical trials testing those two principles. It also evaluates future directions for the field of PARP inhibitor development.

Figure 1.. Structural and functional characteristics of PARP1.

A, poly(ADP-ribose) polymerase 1 (PARP1) is shown with its DNA-binding (DBD), automodification (AD) and catalytic domains. The PARP signature sequence (yellow box within the catalytic domain) comprises the sequence most conserved among PARPs. Crucial residues for nicotinamide adenine dinucleotide (NAD⁺) binding (histidine; H and tyrosine; Y) and for polymerase activity (glutamic acid; E) are indicated. B, consequences of PARP1 activation by DNA damage. Although not shown to simplify the scheme, PARP1 is active in a homodimeric form,. PARP1 detects DNA damage through its DBD. This activates PARP1 to synthesize poly(ADP) ribose (pADPr; yellow beads) on acceptor proteins, including histones and PARP1. Owing to the dense negative charge of pADPr, PARP1 loses affinity for DNA, allowing the recruitment of repair proteins by pADPr to the damaged DNA (blue and purple circles). Poly(ADP-ribose) glycohydrolase (PARG) and possibly ADP-ribose hydrolase 3 (ARH3) hydrolyse pADPr into ADP-ribose molecules and free pADPr. ADP-ribose is further metabolized by the pyrophosphohydrolase NUDIX enzymes into AMP, raising AMP:ATP ratios, which in turn activate the metabolic sensor AMP-activated protein kinase (AMPK). NAD⁺ is replenished by the enzymatic conversion of nicotinamide into NAD⁺ at the expense of phosphoribosylpyrophosphate (PRPP) and ATP. Examples of proteins non-covalently (pADPr-binding proteins) or covalently poly (ADP-ribosyl)ated are shown with the functional consequences of modification. It is important to note that many potential protein acceptors of pADPr remain to be identified owing to the difficulty of purifying pADPr-binding proteins in vivo. PARP inhibitors prevent the synthesis of pADPr and hinder subsequent downstream repair processes, lengthening the lifetime of DNA lesions. ATM, ataxia telangiectasia-mutated; BER, base excision repair; BRCT, BRCA1 carboxy-terminal repeat motif; DNA-PKcs, DNA-protein kinase catalytic subunit; DSB, double-strand break; HR, homologous recombination; NHEJ, non-homologous end joining; NLS, nuclear localisation signal; PP,, inorganic pyrophosphate; SSB, single-strand break; Zn, zinc finger. Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Cancer, 2010,10(4):293–301, copyright (2010).