PARP inhibition: opening up new horizons?

Abstract

Over the last almost 50 years, poly(ADP-ribosyl)ation polymerase (PARP) has sailed the calm seas of clearly arranged basic research and steady gathering of evidence, its relevance remaining elusive for substantial parts of the biomedical community. Although it is widely appreciated that PARP is involved in different steps of DNA repair, research did not pick up pace until two landmark papers were published in 2005 and, subsequently, clinical PARP science gathered momentum. These papers described the mechanism of ‘synthetic lethality’ in BRCA1and BRCA2-mutant cell lines after their exposure to PARP inhibitors. According to this concept, cells carrying BRCA mutations are “profoundly sensitized, to the inhibition of PARP-enzymatic activity” [1,2] owing to their reduced capability of homologues recombination. Since PARP is an integral component of the single-strand break-repair complex, inhibition of PARP results in accumulation of unrepaired single-strand breaks, leading to double-strand breaks during DNA transcription, which normally is ‘repaired’ sufficiently in cells with functioning homologous recombination. Therefore, BRCA-mutant cells that do not harbor this feature sufficiently are prone to chromosomal instability, cell cycle arrest and subsequent apoptosis. The aforementioned sudden acceleration of PARP research was rendered possible by the development of potent hydrophile and nontoxic PARP inhibitors, the ‘freshening wind’ in this narrative. PARP inhibitors became available as early as the 1970s, but one of the crucial developments of second-generation PARP inhibitors was the biand tri-cyclic shape of the molecules that increased the potency of PARP inhibition early in the third millennium [3]. The way was led by the promising preclinical results, thus clinical trials in BRCAmutation carriers were launched in breast and ovarian cancer patients. Those studies also showed encouraging results, and apparitional land was suspected at the horizon of the seascape of cancer treatment. One of the first PARP inhibitors in the clinical setting was olaparib and it has been shown to be active as a single agent in BRCA-mutation carriers with recurrent high-grade serous ovarian cancer [4] and metastatic breast cancer [5]. However, cancers due to BRCA mutations only account for approximately 5% of breast and 5–10% of ovarian cancer cases [6], and thus the apparitional land at the horizon was rather suspected to be islands rather than continents by most, but not all. Enthusiastic reports described a phenomenon called ‘BRCAness’, indicating that cancers even with a nonmutated BRCA1 gene might exhibit a loss of functioning homologues recombination. Several causative mechanisms for BRCAness were proposed, for example aberrant methylation of cytosine residues in CpG dinucleotids of the BRCA1 promoter or the fanconia anaemia gene, both active in homologues recombination [7].