Department of Radiation Oncology, University of Alabama at Birmingham, 1700 6th Avenue South, 176F Hazelrig-Salter Radiation Oncology Center, Room 2232-N, Birmingham, AL 35249-6832, United States.
Department of Radiation Oncology, University of Alabama at Birmingham, 1700 6th Avenue South, 176F Hazelrig-Salter Radiation Oncology Center, Room 2232-N, Birmingham, AL 35249-6832, United States.
Semin Cell Dev Biol. 2017 Mar;63:144-153. doi: 10.1016/j.semcdb.2017.01.007. Epub 2017 Jan 10.
Genomic instability resultant from defective DNA repair mechanisms is a fundamental hallmark of cancer. The poly(ADP-ribose) polymerase (PARP) proteins 1, 2 and 3 catalyze the polymerization of poly(ADP-ribose) and covalent attachment to proteins in a phylogenetically ancient form of protein modification. PARPs play a role in base excision repair, homologous recombination, and non-homologous end joining. The discovery that loss of PARP activity had cytotoxic effects in cells deficient in homologous recombination has sparked a decade of translational research efforts that culminated in the FDA approval of an oral PARP inhibitor for clinical use in patients with ovarian cancer and defective homologous recombination. Five PARP inhibitors are now in late-stage development in clinical trials that are seeking to expand the understanding of targeted therapies and DNA repair defects in human cancer. This review examines the cell biology of PARP, the discovery of synthetic lethality with HR deficiency, the clinical development of PARP inhibitors, and the role of PARP inhibitors in ongoing clinical trials and clinical practice.
基因组不稳定性源于 DNA 修复机制缺陷，是癌症的一个基本特征。多聚（ADP-核糖）聚合酶（PARP）蛋白 1、2 和 3 催化多聚（ADP-核糖）的聚合，并以一种进化上古老的蛋白质修饰形式将其共价连接到蛋白质上。PARPs 在碱基切除修复、同源重组和非同源末端连接中发挥作用。PARP 活性缺失在同源重组缺陷的细胞中具有细胞毒性作用的发现，引发了长达十年的转化研究努力，最终 FDA 批准了一种口服 PARP 抑制剂用于卵巢癌和同源重组缺陷患者的临床应用。目前有五种 PARP 抑制剂正在临床试验的后期阶段，旨在扩大对人类癌症中靶向治疗和 DNA 修复缺陷的理解。这篇综述探讨了 PARP 的细胞生物学、与 HR 缺陷的合成致死性的发现、PARP 抑制剂的临床开发，以及 PARP 抑制剂在正在进行的临床试验和临床实践中的作用。
