Alli Elizabeth, Solow-Cordero David, Casey Stephanie C, Ford James M
Department of Medicine/Oncology, Stanford University School of Medicine, Stanford, California.
Department of Chemical and Systems Biology and Stanford High-Throughput Bioscience Center, Stanford University School of Medicine, Stanford, California.
Cancer Res. 2014 Nov 1;74(21):6205-15. doi: 10.1158/0008-5472.CAN-14-1716. Epub 2014 Sep 12.
Cancers due to germline mutations in the BRCA1 gene tend to lack targets for approved chemoprevention agents. This study aimed at a targeted chemoprevention strategy for BRCA1-associated malignancies. Mutant BRCA1 limits the base-excision DNA repair activity that addresses oxidative DNA damage, the accumulation of which heightens one's risk for cancer. Therefore, we conducted a high-throughput chemical screen to identify drug candidates that could attenuate the inhibitory effects of mutant BRCA1 on this repair activity, thereby describing a new class of DNA repair-activating chemopreventive agents. In the screen design, such drugs functioned by enhancing base-excision DNA repair of oxidative DNA damage in the presence of mutant BRCA1, with minimal cytotoxicity. We identified at least one new agent that decreased malignant properties associated with tumorigenesis, including anchorage-independent growth and tumor progression. This work offers a preclinical proof-of-concept for a wholly new approach to chemoprevention in carriers of BRCA1 mutations as a strategy to reduce the prevalence of BRCA1-associated malignancy.
由BRCA1基因种系突变导致的癌症往往缺乏经批准的化学预防药物的靶点。本研究旨在针对BRCA1相关恶性肿瘤制定一种靶向化学预防策略。突变型BRCA1会限制碱基切除DNA修复活性，而该活性可处理氧化性DNA损伤，氧化性DNA损伤的积累会增加患癌风险。因此，我们进行了一项高通量化学筛选，以鉴定能够减弱突变型BRCA1对这种修复活性的抑制作用的候选药物，从而描述了一类新型的DNA修复激活化学预防药物。在筛选设计中，此类药物通过在存在突变型BRCA1的情况下增强氧化性DNA损伤的碱基切除DNA修复来发挥作用，且细胞毒性最小。我们鉴定出至少一种新药物，它可降低与肿瘤发生相关的恶性特性，包括不依赖贴壁生长和肿瘤进展。这项工作为BRCA1突变携带者的化学预防提供了一种全新方法的临床前概念验证，作为降低BRCA1相关恶性肿瘤患病率的一种策略。
