Poly(ADP-Ribose) polymerase (PARP) inhibitors: Exploiting a synthetic lethal strategy in the clinic

Abstract

Poly(ADP-ribose) polymerase (PARP) is an attractive antitumor target because of its vital role in DNA repair. The homologous recombination (HR) DNA repair pathway is critical for the repair of DNA double-strand breaks and HR deficiency leads to a dependency on error-prone DNA repair mechanisms, with consequent genomic instability and oncogenesis. Tumor-specific HR defects may be exploited through a synthetic lethal approach for the application of anticancer therapeutics, including PARP inhibitors. This theory proposes that targeting genetically defective tumor cells with a specific molecular therapy that inhibits its synthetic lethal gene partner should result in selective tumor cell killing. The demonstration of single-agent antitumor activity and the wide therapeutic index of PARP inhibitors in BRCA1 and BRCA2 mutation carriers with advanced cancers provide strong evidence for the clinical application of this approach. Emerging data also indicate that PARP inhibitors may be effective in sporadic cancers bearing HR defects, supporting a substantially wider role for PARP inhibitors. Drugs targeting this enzyme are now in pivotal clinical trials in patients with sporadic cancers. In this article, the evidence supporting this antitumor synthetic lethal strategy with PARP inhibitors is reviewed, evolving resistance mechanisms and potential molecular predictive biomarker assays are discussed, and the future development of these agents is envisioned. CA Cancer J Clin 2011;61:31-49.

Poly(ADP-ribosyl)ation of p53 induces gene-specific transcriptional repression of MTA1

“…These observations indicate that inhibition of PARP-1 may cause disturbances in gene expression that may drive the stimulation of a genetic network that enhances oncogenic potential. More intriguingly, several preclinical studies have reported that PARP inhibitors are more effective in BRCA-deficient cells than in wild-type BRCA cells (Yap et al, 2011). Furthermore, a recent trial showed that iniparib failed to prolong survival in metastatic, triple-negative breast cancer (O'Shaughnessy et al, 2011).…”

“…Therefore, PARP inhibitors are developed to target a wide spectrum of cancers or to sensitize cancer cells to anticancer therapy. A variety of PARP-1 inhibitors, including Iniparib, Olaparib and Veliparib, are currently in clinical trials (Yap et al, 2011). However, much attention should be given to our observation that knockdown or chemical inhibition of PARP1 decreased the 5-FU-induced p53 binding on the promoter of MTA1, and subsequently recovered the expression level of the MTA1 gene (Figures 5c and 6a).…”

Ovarian Cancer: BRCA Genetics Reveals Targets for New Therapies

“…PARP inhibitors could restore BRCA1/2 function through genetic or epigenetic mechanisms [60]. Long-term PARP inhibition per se is also cause of tumor resistance, possibly through PARP gene mutations that alter interaction with inhibitors, or up-regulation of alternative DNA repair or cell proliferation pathways [61]. In summary, PARP inhibitors, the leading agents of synthetic lethality, are precious tools for killing tumor cells after the acquisition of resistance to previously employed therapies.…”

Pancreatic ductal adenocarcinoma in BRCA2 mutation carriers

“…Based on this principle, PARP1/2 inhibitors (PARPi) have been developed to target tumor cells in BRCA1/2 mutation carriers, in which loss-of-function of both HR and base excision repair leaves DNA doublestrand breaks unrepaired, leading to accumulation of DNA damage, genomic instability and ultimately cell death (Bryant et al 2005, Farmer et al 2005, Sandhu et al 2010, Yap et al 2011, Dhillon et al 2016. Moreover, PARPi exert direct DNA toxicity by trapping PARP1 (and PARP2) at damaged DNA where the PARP-DNA complexes are more cytotoxic than unrepaired single-strand DNA breaks themselves (Murai et al 2012).…”