Trial watch - inhibiting PARP enzymes for anticancer therapy.
Poly(ADP-ribose) polymerases (PARPs) are a members of family of enzymes that catalyze poly(ADP-ribosyl)ation (PARylation) and/or mono(ADP-ribosyl)ation (MARylation), two post-translational protein modifications involved in crucial cellular processes including (but not limited to) the DNA damage response (DDR). PARP1, the most abundant family member, is a nuclear protein that is activated upon sensing distinct types of DNA damage and contributes to their resolution by PARylating multiple DDR players. Recent evidence suggests that, along with DDR, activated PARP1 mediates a series of prosurvival and proapoptotic processes aimed at preserving genomic stability. Despite this potential oncosuppressive role, upregulation and/or overactivation of PARP1 or other PARP enzymes has been reported in a variety of human neoplasms. Over the last few decades, several pharmacologic inhibitors of PARP1 and PARP2 have been assessed in preclinical and clinical studies showing potent antineoplastic activity, particularly against homologous recombination (HR)-deficient ovarian and breast cancers. In this Trial Watch, we describe the impact of PARP enzymes and PARylation in cancer, discuss the mechanism of cancer cell killing by PARP1 inactivation, and summarize the results of recent clinical studies aimed at evaluating the safety and therapeutic profile of PARP inhibitors in cancer patients.
Regina Elena National Cancer Institute , Rome, Italy.
Antonella
A
Sistigu
Regina Elena National Cancer Institute , Rome, Italy.
Gwenola
G
Manic
Université Paris-Sud/Paris XI, Le Kremlin-Bicêtre, France; INSERM, UMRS1138, Paris, France; Equipe 11 labelisée par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers, Paris, France; Gustave Roussy Cancer Campus, Villejuif, France.
Florine
F
Obrist
Regina Elena National Cancer Institute, Rome, Italy; Department of Biology, University of Rome "TorVergata", Rome, Italy.
Ilio
I
Vitale
Cell death; DNA damage; NAD; drug resistance; metabolism; olaparib; synthetic lethality