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Lessons learned from understanding chemotherapy resistance in epithelial tubo-ovarian carcinoma from BRCA1and BRCA2mutation carriers
Seminars in Cancer Biology ( IF 14.5 ) Pub Date : 2020-08-19 , DOI: 10.1016/j.semcancer.2020.08.005
Cécile Le Page 1 , Setor Amuzu 2 , Kurosh Rahimi 3 , Walter Gotlieb 4 , Jiannis Ragoussis 2 , Patricia N Tonin 5
Affiliation  

BRCA1 and BRCA2 are multi-functional proteins and key factors for maintaining genomic stability through their roles in DNA double strand break repair by homologous recombination, rescuing stalled or damaged DNA replication forks, and regulation of cell cycle DNA damage checkpoints. Impairment of any of these critical roles results in genomic instability, a phenotypic hallmark of many cancers including breast and epithelial ovarian carcinomas (EOC). Damaging, usually loss of function germline and somatic variants in BRCA1 and BRCA2, are important drivers of the development, progression, and management of high-grade serous tubo-ovarian carcinoma (HGSOC). However, mutations in these genes render patients particularly sensitive to platinum-based chemotherapy, and to the more innovative targeted therapies with poly-(ADP-ribose) polymerase inhibitors (PARPis) that are targeted to BRCA1/BRCA2 mutation carriers. Here, we reviewed the literature on the responsiveness of BRCA1/2-associated HGSOC to platinum-based chemotherapy and PARPis, and propose mechanisms underlying the frequent development of resistance to these therapeutic agents.



中文翻译:

从 BRCA1 和 BRCA2 突变携带者了解上皮性输卵管卵巢癌对化疗耐药的经验教训

BRCA1 和 BRCA2 是多功能蛋白,是维持基因组稳定性的关键因素,它们通过同源重组在 DNA 双链断裂修复、拯救停滞或受损的 DNA 复制叉以及调节细胞周期 DNA 损伤检查点等方面发挥作用。任何这些关键作用的损害都会导致基因组不稳定,这是包括乳腺癌和上皮性卵巢癌 (EOC) 在内的许多癌症的表型标志。损坏,通常是BRCA1BRCA2中种系和体细胞变异的功能丧失,是高级别浆液性输卵管卵巢癌 (HGSOC) 的发展、进展和管理的重要驱动因素。然而,这些基因的突变使患者对铂类化疗特别敏感,并且对针对BRCA1/BRCA2突变携带者的多聚(ADP-核糖)聚合酶抑制剂 (PARPis) 的更具创新性的靶向治疗特别敏感。在这里,我们回顾了有关 BRCA1/2 相关 HGSOC 对铂类化疗和 PARPis 的反应性的文献,并提出了对这些治疗药物频繁产生耐药性的机制。

更新日期:2020-08-19
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