Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers.
Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers.
复制标题
核糖体蛋白 S6 的磷酸化赋予 BRCA1 缺陷型癌症对 PARP 抑制剂的耐药性。
DOI：
10.18632/oncotarget.1952
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发表时间：
2014-05-30
期刊：
影响因子：
--
通讯作者：
Yang Q
中科院分区：
文献类型：
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作者：
Sun CK;Zhang F;Xiang T;Chen Q;Pandita TK;Huang Y;Hu MC;Yang Q
抑制聚（adp -核糖）聚合酶（PARP）是治疗BRCA1缺陷癌症的一种很有前景的治疗策略，然而，耐药的发展限制了临床疗效。之前我们发现BRCA1-AKT1通路有助于肿瘤发生，并且AKT1/mTOR是brca1缺陷癌症的新治疗靶点。在这里，我们报道了在抵抗PARP抑制的BRCA1缺陷细胞中，mTOR下游效应物核糖体蛋白S6的磷酸化大大增加。在PARP抑制剂治疗期间，S6的磷酸化与DNA损伤和修复信号有关。在BRCA1缺失的细胞中，S6缺乏所有五个磷酸化位点的表达使细胞对PARP抑制剂敏感，并增加DNA损伤信号。此外，S6突变可减少brca1缺失引起的小鼠肿瘤形成。雷帕霉素抑制S6磷酸化可恢复PARP对耐药细胞的敏感性。雷帕霉素和PARP抑制剂联合治疗可有效抑制小鼠brca1缺陷肿瘤的生长。这些结果为BRCA1缺陷癌症获得耐药的新机制提供了证据，并提出了一种新的治疗策略来规避耐药。
Inhibition of poly(ADP-ribose) polymerase (PARP) is a promising therapeutic strategy for BRCA1 deficient cancers, however, the development of drug resistance limits clinical efficacy. Previously we found that the BRCA1-AKT1 pathway contributes to tumorigenesis and that the AKT1/mTOR is a novel therapeutic target for BRCA1-deficient cancers. Here, we report that phosphorylation of ribosomal protein S6, a mTOR downstream effector, is greatly increased in BRCA1 deficient cells resistant to PARP inhibition. Phosphorylation of S6 is associated with DNA damage and repair signaling during PARP inhibitor treatment. In BRCA1 deficient cells, expression of S6 lacking all five phosphorylatable sites renders the cells sensitive to PARP inhibitor and increases DNA damage signals. In addition, the S6 mutations reduce tumor formation induced by Brca1-deficiency in mice. Inhibition of S6 phosphorylation by rapamycin restores PARP sensitivity to resistant cells. Combined treatment with rapamycin and PARP inhibitor effectively suppresses BRCA1-deficient tumor growth in mice. These results provide evidence for a novel mechanism by which BRCA1 deficient cancers acquire drug resistance and suggest a new therapeutic strategy to circumvent resistance.