“Back to a false normality”: new intriguing mechanisms of resistance to PARP inhibitors
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Lorena Incorvaia1,*, Francesc Passiglia1,*, Sergio Rizzo1,*, Antonio Galvano1,*, Angela Listì1, Nadia Barraco1, Rossella Maragliano1, Valentina Calò1, Clara Natoli2, Marcello Ciaccio3, Viviana Bazan1,** and Antonio Russo1,**
1 Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
2 Department of Medical, Oral and Biotechnological Sciences, Centre of Ageing Sciences and Translational Medicine - CESI-MeT University “G. D’Annunzio”, Chieti, Italy
3 Section of Clinical Biochemistry and Clinical Molecular Medicine, Department of Biopathology and Medical Biotechnology, University of Palermo - U.O.C. Laboratory Medicine - CoreLab, Policlinico University Hospital, Palermo, Italy
* These authors have contributed equally to this work
** Senior authors
Antonio Russo, email:
Keywords: PARP inhibitors, BRCA1-2, resistance
Received: November 10, 2016 Accepted: December 23, 2016 Published: December 31, 2016
Several evidences have shown that BRCA mutations increased tumor-cells sensitivity to PARP inhibitors by synthetic lethality leading to an accelerated development of several compounds targeting the PARP enzymes system as anticancer agents for clinical setting. Most of such compounds have been investigated in ovarian and breast cancer, showing promising efficacy in BRCA-mutated patients. Recently clinical studies of PARP-inhibitors have been extended across different tumor types harboring BRCA-mutations, including also “BRCA-like” sporadic tumors with homologous recombination deficiency (HRD). This review summarizes the biological background underlying PARP-inhibition, reporting the results of the most relevant clinical trials carried out in patients treated with PARP inhibitors alone or in combination with chemotherapy. Molecular mechanisms responsible for the occurrence of both primary and acquired resistance have been elucidated, in order to support the development of new treatment strategies.
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