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Review
. 2017 Apr 4;8(14):23891-23904.
doi: 10.18632/oncotarget.14409.

"Back to a false normality": new intriguing mechanisms of resistance to PARP inhibitors

Lorena Incorvaia  1 , Francesc Passiglia  1 , Sergio Rizzo  1 , Antonio Galvano  1 , Angela Listì  1 , Nadia Barraco  1 , Rossella Maragliano  1 , Valentina Calò  1 , Clara Natoli  2 , Marcello Ciaccio  3 , Viviana Bazan  1 , Antonio Russo  1
Affiliations
Review

"Back to a false normality": new intriguing mechanisms of resistance to PARP inhibitors

Lorena Incorvaia et al. Oncotarget. .

Abstract

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.

Keywords: BRCA1-2; PARP inhibitors; resistance.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declared no potential financial conflicts of interest.

Figures

Figure 1
Figure 1. PARP inhibitor acquired resistance mechanism
Based from pre-clinical studies, several alteration are responsible of partial or complete restoration of the HR repair function: secondary mutations in BRCA1-2; loss of 53BP1 protein function; Pgp over-expression and PARPi efflux.
See this image and copyright information in PMC

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