PARP inhibitors in breast cancer: BRCA and beyond.
PARP inhibitors in breast cancer: BRCA and beyond.
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作者：
J. Rios;S. Puhalla
DNA修复对于正常细胞和癌细胞的生存都是至关重要的。一套复杂的信号通路检测单链和双链DNA断裂，并在损伤太大而无法修复的情况下调节DNA修复或细胞凋亡。聚(二磷酸腺苷[ADP]-核糖)聚合酶(PARP)通过碱基切除修复途径在碱基损伤修复中发挥关键作用。对PARP的药理抑制会导致某些DNA修复途径突变的肿瘤细胞死亡--例如双链断裂修复的BRCA途径--当与导致DNA损伤的化疗相结合时。人们正在研究PARP抑制剂，作为一种单一疗法，用于治疗BRCA 1/2突变的患者；用于治疗三阴性乳腺癌，因为它与BRCA1突变的恶性肿瘤分子相似；以及作为一种增强化疗和放射的DNA损伤效应的策略。本文的目的是回顾在上述环境中使用PARP抑制剂的临床前数据和原理，以及这些药物在乳腺癌治疗中的临床开发现状，以及该领域未来的研究方向。通过搜索PubMed，Clinicaltrials.gov，以及美国临床肿瘤学会年会和圣安东尼奥乳腺癌研讨会的论文集来确定试验。
DNA repair is essential for the survival of both normal and cancer cells. An elaborate set of signaling pathways detect single-strand and double-strand DNA breaks and mediate either DNA repair or apoptosis if the damage is too great to repair. Poly(adenosine diphosphate [ADP]-ribose) polymerases (PARPs) play a key role in the repair of base damage via the base excision repair pathway. Pharmacological inhibition of PARP induces cell death in tumors with mutations in certain DNA repair pathways--such as the BRCA pathways of double-strand break repair--and when combined with chemotherapies that cause DNA damage. PARP inhibitors are being investigated as a monotherapy for the treatment of patients with BRCA 1/2 mutations; in the treatment of triple-negative breast cancer, because of its molecular similarities to BRCA1-mutated malignancies; and as a strategy to potentiate the DNA-damaging effects of chemotherapy and radiation. The aim of this article is to review the preclinical data and rationale for PARP inhibitor use in the aforementioned settings, as well as the current status of the clinical development of these agents in the treatment of breast cancer, along with future directions for research in this field. Trials have been identified via searches of PubMed, clinicaltrials.gov, and the Proceedings of the American Society of Clinical Oncology Annual Meeting and the San Antonio Breast Cancer Symposium.