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Biochim Biophys Acta. 2014 Aug;1846(1):201-15. doi: 10.1016/j.bbcan.2014.07.004. Epub 2014 Jul 12.

Inhibition of poly(ADP-ribosyl)ation in cancer: old and new paradigms revisited.

Author information

1
Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy; Laboratory of Molecular Pharmacology, Candiolo Cancer Institute, FPO IRCCS, 10060 Candiolo, Torino, Italy.
2
Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy; Laboratory of Molecular Pharmacology, Candiolo Cancer Institute, FPO IRCCS, 10060 Candiolo, Torino, Italy. Electronic address: livio.trusolino@unito.it.

Abstract

Inhibitors of poly(ADP-ribose) polymerases actualized the biological concept of synthetic lethality in the clinical practice, yielding a paradigmatic example of translational medicine. The profound sensitivity of tumors with germline BRCA mutations to PARP1/2 blockade owes to inherent defects of the BRCA-dependent homologous recombination machinery, which are unleashed by interruption of PARP DNA repair activity and lead to DNA damage overload and cell death. Conversely, aspirant BRCA-like tumors harboring somatic DNA repair dysfunctions (a vast entity of genetic and epigenetic defects known as "BRCAness") not always align with the familial counterpart and appear not to be equally sensitive to PARP inhibition. The acquisition of secondary resistance in initially responsive patients and the lack of standardized biomarkers to identify "BRCAness" pose serious threats to the clinical advance of PARP inhibitors; a feeling is also emerging that a BRCA-centered perspective might have missed the influence of additional, not negligible and DNA repair-independent PARP contributions onto therapy outcome. While regulatory approval for PARP1/2 inhibitors is still pending, novel therapeutic opportunities are sprouting from different branches of the PARP family, although they remain immature for clinical extrapolation. This review is an endeavor to provide a comprehensive appraisal of the multifaceted biology of PARPs and their evolving impact on cancer therapeutics.

KEYWORDS:

BRCAness; DNA repair; Poly(ADP-ribose) polymerase; Synthetic lethality; Tankyrase; Targeted cancer therapies

PMID:
25026313
DOI:
10.1016/j.bbcan.2014.07.004
[Indexed for MEDLINE]
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