Crosstalk of DNA double-strand break repair pathways in poly(ADP-ribose) polymerase inhibitor treatment of breast cancer susceptibility gene 1/2-mutated cancer.
Crosstalk of DNA double-strand break repair pathways in poly(ADP-ribose) polymerase inhibitor treatment of breast cancer susceptibility gene 1/2-mutated cancer.
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DOI：
10.1111/cas.13530
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发表时间：
2018-04
期刊：
影响因子：
5.7
通讯作者：
Miki Y
中科院分区：
文献类型：
--
作者：
Sunada S;Nakanishi A;Miki Y
乳腺癌易感基因1或2（BRCA 1或BRCA 2）的生殖系突变显著增加遗传性乳腺癌和卵巢癌综合征（HBOC）的癌症风险。这两种基因都在DNA双链断裂（DSB）修复过程的同源重组（HR）途径中发挥作用。因此，癌细胞特有的DNA修复缺陷为聚（ADP-核糖）聚合酶（PARP）抑制剂诱导的合成致死性带来了治疗优势。基于PARP抑制剂的疗法最初导致癌症致死，但已发现获得性耐药机制，需要阐明。特别是，必须详细了解DNA损伤和修复的机制，以PARP抑制剂治疗。进一步的研究显示了BRCA 1/2的作用及其与DSB修复系统中其他分子的关联。值得注意的是，BRCA 1缺陷细胞中选择的修复途径可能与PARP抑制剂处理后BRCA 2缺陷细胞中的修复途径完全不同。本文综述了PARP抑制剂通过DSB修复途径和后续修复过程的合成致死性和获得性耐药机制。此外，最近的知识的阻力机制进行了讨论。我们的模型应该有助于开发新的治疗策略。
Germline mutations in breast cancer susceptibility gene 1 or 2 (BRCA1 or BRCA2) significantly increase cancer risk in hereditary breast and ovarian cancer syndrome (HBOC). Both genes function in the homologous recombination (HR) pathway of the DNA double‐strand break (DSB) repair process. Therefore, the DNA‐repair defect characteristic of cancer cells brings about a therapeutic advantage for poly(ADP‐ribose) polymerase (PARP) inhibitor‐induced synthetic lethality. PARP inhibitor‐based therapeutics initially cause cancer lethality but acquired resistance mechanisms have been found and need to be elucidated. In particular, it is essential to understand in detail the mechanism of DNA damage and repair to PARP inhibitor treatment. Further investigations have shown the roles of BRCA1/2 and its associations to other molecules in the DSB repair system. Notably, the repair pathway chosen in BRCA1‐deficient cells could be entirely different from that in BRCA2‐deficient cells after PARP inhibitor treatment. The present review describes synthetic lethality and acquired resistance mechanisms to PARP inhibitor through the DSB repair pathway and subsequent repair process. In addition, recent knowledge of resistance mechanisms is discussed. Our model should contribute to the development of novel therapeutic strategies.
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影响因子：
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