Incorvaia Lorena, Passiglia Francesc, Rizzo Sergio, Galvano Antonio, Listì Angela, Barraco Nadia, Maragliano Rossella, Calò Valentina, Natoli Clara, Ciaccio Marcello, Bazan Viviana, Russo Antonio
Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy.
Department of Medical, Oral and Biotechnological Sciences, Centre of Ageing Sciences and Translational Medicine - CESI-MeT University "G. D'Annunzio", Chieti, Italy.
Oncotarget. 2017 Apr 4;8(14):23891-23904. doi: 10.18632/oncotarget.14409.
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.
多项证据表明，BRCA突变通过合成致死性增加了肿瘤细胞对PARP抑制剂的敏感性，从而促使几种靶向PARP酶系统的化合物加速研发，作为临床环境中的抗癌药物。此类化合物大多已在卵巢癌和乳腺癌中进行了研究，在BRCA突变患者中显示出有前景的疗效。最近，PARP抑制剂的临床研究已扩展到不同类型的携带BRCA突变的肿瘤，包括具有同源重组缺陷（HRD）的“BRCA样”散发性肿瘤。本综述总结了PARP抑制的生物学背景，报告了单用PARP抑制剂或与化疗联合治疗患者所开展的最相关临床试验的结果。已阐明了导致原发性和获得性耐药发生的分子机制，以支持新治疗策略的开发。
