Ang Yvonne L E, Tan David S P
Department of Hematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore.
Department of Hematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Curr Probl Cancer. 2017 Jul-Aug;41(4):273-286. doi: 10.1016/j.currproblcancer.2017.02.008. Epub 2017 Mar 14.
PARP inhibitors demonstrate synthetic lethality in tumors with BRCA1/2 mutations and other homologous recombination repair deficiencies by interfering with DNA repair and causing direct toxicity to DNA through PARP trapping. PARP inhibitors have been shown to be beneficial in the treatment of BRCA1/2-mutated ovarian cancers, which has led to a shift in the treatment paradigm of this disease. Further studies to establish the role of PARP inhibitors during earlier stages of treatment are ongoing. The use of PARP inhibitors in other cancers with homologous recombination repair deficiencies, such as breast cancer and prostate cancer, is gradually evolving as well, including their use in the neoadjuvant and adjuvant settings. PARP inhibitor combination strategies with chemotherapy, targeted agents, radiotherapy, and immunotherapy are also being explored. The role of predictive biomarkers, including molecular signatures and homologous recombination deficiency scores based on loss of heterozygosity and other structural genomic aberrations, will be crucial to improved patient stratification to enhance the clinical utility of PARP inhibitors. This may also allow the use of PARP inhibitors to be extended beyond tumors with specific homologous recombination DNA repair gene mutations in the future. An improved understanding of the mechanisms underlying PARP inhibitor resistance will also be important to enable the development of new approaches to increase efficacy. This is a field rich in opportunity, and the coming years should see a better understanding of which patients we should be treating with PARP inhibitors and where these agents should come in over the course of treatment.
聚（ADP-核糖）聚合酶（PARP）抑制剂通过干扰DNA修复并通过PARP捕获对DNA造成直接毒性，在具有BRCA1/2突变和其他同源重组修复缺陷的肿瘤中表现出合成致死性。PARP抑制剂已被证明对治疗BRCA1/2突变的卵巢癌有益，这导致了该疾病治疗模式的转变。目前正在进行进一步的研究以确定PARP抑制剂在治疗早期阶段的作用。PARP抑制剂在其他具有同源重组修复缺陷的癌症（如乳腺癌和前列腺癌）中的应用也在逐渐发展，包括其在新辅助和辅助治疗中的应用。PARP抑制剂与化疗、靶向药物、放疗和免疫治疗的联合策略也在探索中。预测性生物标志物的作用，包括基于杂合性缺失和其他结构基因组畸变的分子特征和同源重组缺陷评分，对于改善患者分层以提高PARP抑制剂的临床效用至关重要。这也可能使PARP抑制剂的应用在未来扩展到具有特定同源重组DNA修复基因突变的肿瘤之外。更好地理解PARP抑制剂耐药的潜在机制对于开发提高疗效的新方法也很重要。这是一个充满机遇的领域，未来几年我们应该会更清楚地了解哪些患者应该接受PARP抑制剂治疗，以及这些药物在治疗过程中应该处于什么位置。
