Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Exp Mol Med. 2021 Jan;53(1):42-51. doi: 10.1038/s12276-021-00557-3. Epub 2021 Jan 25.
Homologous recombination (HR) repair deficiency impairs the proper maintenance of genomic stability, thus rendering cancer cells vulnerable to loss or inhibition of DNA repair proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1). Inhibitors of nuclear PARPs are effective therapeutics for a number of different types of cancers. Here we review key concepts and current progress on the therapeutic use of PARP inhibitors (PARPi). PARPi selectively induce synthetic lethality in cancer cells with homologous recombination deficiencies (HRDs), the most notable being cancer cells harboring mutations in the BRCA1 and BRCA2 genes. Recent clinical evidence, however, shows that PARPi can be effective as cancer therapeutics regardless of BRCA1/2 or HRD status, suggesting that a broader population of patients might benefit from PARPi therapy. Currently, four PARPi have been approved by the Food and Drug Administration (FDA) for the treatment of advanced ovarian and breast cancer with deleterious BRCA mutations. Although PARPi have been shown to improve progression-free survival, cancer cells inevitably develop resistance, which poses a significant obstacle to the prolonged use of PARP inhibitors. For example, somatic BRCA1/2 reversion mutations are often identified in patients with BRCA1/2-mutated cancers after treatment with platinum-based therapy, causing restoration of HR capacity and thus conferring PARPi resistance. Accordingly, PARPi have been studied in combination with other targeted therapies to overcome PARPi resistance, enhance PARPi efficacy, and sensitize tumors to PARP inhibition. Moreover, multiple clinical trials are now actively underway to evaluate novel combinations of PARPi with other anticancer therapies for the treatment of PARPi-resistant cancer. In this review, we highlight the mechanisms of action of PARP inhibitors with or without BRCA1/2 defects and provide an overview of the ongoing clinical trials of PARPi. We also review the current progress on PARPi-based combination strategies and PARP inhibitor resistance.
同源重组 (HR) 修复缺陷会损害基因组稳定性的适当维持，从而使癌细胞容易失去或抑制 DNA 修复蛋白，如聚 (ADP-核糖) 聚合酶-1 (PARP-1)。PARP 的核抑制剂是多种不同类型癌症的有效治疗药物。在这里，我们回顾了 PARP 抑制剂 (PARPi) 治疗应用的关键概念和最新进展。PARPi 选择性地在具有同源重组缺陷 (HRD) 的癌细胞中诱导合成致死性，最显著的是携带 BRCA1 和 BRCA2 基因突变的癌细胞。然而，最近的临床证据表明，PARPi 可以作为癌症治疗药物有效，无论 BRCA1/2 或 HRD 状态如何，这表明更广泛的患者群体可能受益于 PARPi 治疗。目前，四种 PARPi 已被美国食品和药物管理局 (FDA) 批准用于治疗具有有害 BRCA 突变的晚期卵巢癌和乳腺癌。尽管 PARPi 已被证明可改善无进展生存期，但癌细胞不可避免地会产生耐药性，这对 PARP 抑制剂的长期使用构成了重大障碍。例如，在接受基于铂的治疗后，BRCA1/2 突变的癌症患者中经常会发现体细胞 BRCA1/2 回复突变，导致 HR 能力的恢复，从而赋予 PARPi 耐药性。因此，PARPi 已与其他靶向治疗联合研究，以克服 PARPi 耐药性，增强 PARPi 疗效，并使肿瘤对 PARP 抑制敏感。此外，目前正在进行多项临床试验，以评估 PARPi 与其他抗癌疗法联合用于治疗 PARPi 耐药性癌症的效果。在这篇综述中，我们强调了 PARPi 与 BRCA1/2 缺陷的作用机制，并概述了 PARPi 的正在进行的临床试验。我们还回顾了基于 PARPi 的联合策略和 PARP 抑制剂耐药性的最新进展。
