Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
Institute of Clinical Pharmacology, Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, 410078, China.
Acta Pharmacol Sin. 2021 Dec;42(12):1970-1980. doi: 10.1038/s41401-020-00604-1. Epub 2021 Feb 15.
PARP inhibitors are a group of inhibitors targeting poly(ADP-ribose) polymerases (PARP1 or PARP2) involved in DNA repair and transcriptional regulation, which may induce synthetic lethality in BRCAness tumors. Systematic analyzes of genomic sequencing in prostate cancer show that ~10%-19% of patients with primary prostate cancer have inactivated DNA repair genes, with a notably higher proportion of 23%-27% in patients with metastatic castration-resistant prostate cancer (mCRPC). These characteristic genomic alterations confer possible vulnerability to PARP inhibitors in patients with mCRPC who benefit only modestly from other therapies. However, only a small proportion of patients with mCRPC shows sensitivity to PARP inhibitors, and these sensitive patients cannot be fully identified by existing response prediction biomarkers. In this review, we provide an overview of the potential response prediction biomarkers and synergistic combinations studied in the preclinical and clinical stages, which may expand the population of patients with prostate cancer who may benefit from PARP inhibitors.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂是一组针对参与 DNA 修复和转录调控的聚（ADP-核糖）聚合酶（PARP1 或 PARP2）的抑制剂，可能在 BRCAness 肿瘤中诱导合成致死。对前列腺癌的基因组测序进行系统分析表明，~10%-19%的原发性前列腺癌患者存在 DNA 修复基因失活，转移性去势抵抗性前列腺癌（mCRPC）患者的比例明显更高，为 23%-27%。这些特征性的基因组改变使 mCRPC 患者对 PARP 抑制剂可能具有潜在的脆弱性，而这些患者从其他治疗中获益甚微。然而，只有一小部分 mCRPC 患者对 PARP 抑制剂敏感，而这些敏感患者不能通过现有的反应预测生物标志物完全识别。在这篇综述中，我们概述了在临床前和临床阶段研究的潜在反应预测生物标志物和协同组合，这些可能会扩大可能从 PARP 抑制剂中获益的前列腺癌患者群体。
