Department of Pathology and Laboratory Medicine and The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA.
Transl Res. 2012 Sep;160(3):178-97. doi: 10.1016/j.trsl.2012.01.022. Epub 2012 Feb 9.
Defects in components of DNA repair pathways are responsible for numerous hereditary cancer syndromes and are also common in many sporadic malignancies. Inherited mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 or components of the Fanconi anemia (FA) complex incite genomic instability and predispose to malignancy. The products of the BRCA and FA genes participate in a conserved DNA damage repair pathway that is responsible for repairing interstrand crosslinks and double-strand DNA breaks by homologous recombination. While the genetic instability resulting from FA/BRCA dysfunction contributes to cancer pathogenesis, deficiency of these genes also lends to therapeutic exploitation. Crosslinking agents and ionizing radiation induce damage in cancer cells that requires the FA/BRCA pathway to be resolved; thus cancers that are deficient in BRCA1, BRCA2, or any other component of the FA/BRCA pathway are hypersensitive to these agents. Moreover, emerging synthetic lethal strategies offer opportunities to selectively target cancer cells with defects in homologous recombination. Conversely, enhanced activity of the FA/BRCA pathway is responsible for acquired resistance to specific therapeutic agents, suggesting that both dysfunction and hyperfunction of the FA/BRCA repair machinery are rational targets for cancer therapy. Selection of specific cytotoxic agents based on repair capacity may improve responses and enable personalized cytotoxic chemotherapy. This article reviews the FA/BRCA pathway and current approaches to identify deficiencies within it, discusses synthetic lethality and enhanced repair capacity as causes of therapeutic hypersensitivity and resistance, respectively, and highlights recent studies that have linked FA/BRCA pathway function with therapeutic efficacy.
DNA 修复途径成分的缺陷导致了许多遗传性癌症综合征，并且在许多散发性恶性肿瘤中也很常见。乳腺癌易感基因 BRCA1 和 BRCA2 或范可尼贫血 (FA) 复合物的遗传突变会引发基因组不稳定，并导致恶性肿瘤。BRCA 和 FA 基因的产物参与保守的 DNA 损伤修复途径，该途径负责通过同源重组修复链间交联和双链 DNA 断裂。虽然 FA/BRCA 功能障碍导致的遗传不稳定性有助于癌症发病机制，但这些基因的缺乏也为治疗利用提供了机会。交联剂和电离辐射会在癌细胞中引起需要 FA/BRCA 途径来解决的损伤；因此，BRCA1、BRCA2 或 FA/BRCA 途径的任何其他成分缺失的癌症对这些药物非常敏感。此外，新兴的合成致死策略为利用同源重组缺陷的癌细胞提供了选择性靶向的机会。相反，FA/BRCA 途径的活性增强是对特定治疗药物产生获得性耐药的原因，这表明 FA/BRCA 修复机制的功能障碍和功能亢进都是癌症治疗的合理靶点。基于修复能力选择特定的细胞毒性药物可能会改善反应并实现个性化细胞毒性化疗。本文综述了 FA/BRCA 途径和目前识别其缺陷的方法，讨论了合成致死性和增强的修复能力分别作为治疗敏感性和耐药性的原因，并强调了最近将 FA/BRCA 途径功能与治疗效果联系起来的研究。
