Dual mTORC1/2 Inhibition as a Novel Strategy for the Resensitization and Treatment of Platinum-Resistant Ovarian Cancer.
Dual mTORC1/2 Inhibition as a Novel Strategy for the Resensitization and Treatment of Platinum-Resistant Ovarian Cancer.
复制标题
DOI：
10.1158/1535-7163.mct-15-0926
复制
发表时间：
2016-07
影响因子：
5.7
通讯作者：
Schneider RJ
中科院分区：
文献类型：
--
作者：
Musa F;Alard A;David-West G;Curtin JP;Blank SV;Schneider RJ
对mTOR复合物mTORC 1和2的抑制剂的临床开发有相当大的兴趣。由于mTORC 1及其下游mRNA翻译效应物可以保护免受遗传毒性DNA损伤，我们研究了mTORC 1和mTORC 1/2在组织培养和浆液性卵巢癌动物肿瘤模型中逆转铂类耐药的能力。研究了细胞存活、肿瘤生长、PI 3 K-AKT-mTOR通路信号传导、DNA损伤和修复反应（DDR）基因表达和翻译控制。我们发现，铂耐药OVCAR-3卵巢癌细胞通过mTOR抑制对培养物中低水平的卡铂重新敏感，表明用mTORC 1抑制剂依维莫司或mTORC 1/2抑制剂PP 242治疗后存活率降低。铂耐药性与AKT和CHK 1的激活磷酸化、4 E-BP 1的失活磷酸化有关，4 E-BP 1是eIF 4 E的负调节因子，其促进帽依赖性mRNA翻译增加和CHK 1和BRCA 1蛋白水平增加。与用卡铂加仅抑制mTORC 1的依维莫司治疗的动物相比，用卡铂加mTORC 1/2抑制治疗的具有铂抗性OVCAR-3肿瘤的动物具有显著更长的中位存活期和显著减少的转移。通过卡铂治疗抑制mTORC 1/2减少肿瘤生长、转移和增加存活与AKT活化磷酸化减少和4 E-BP 1低磷酸化（活化）增加相关。我们得出结论，mTORC 1/2抑制在逆转肿瘤铂类耐药方面上级于mTORC 1抑制，并强烈损害AKT活化、DNA修复反应和翻译，促进铂类耐药背景下生存率的改善。
There is considerable interest in the clinical development of inhibitors of mTOR complexes mTORC1 and 2. Because mTORC1 and its downstream mRNA translation effectors may protect against genotoxic DNA damage, we investigated the inhibition of mTORC1 and mTORC1/2 in the ability to reverse platinum resistance in tissue culture and in animal tumor models of serous ovarian cancer. Cell survival, tumor growth, PI3K-AKT-mTOR pathway signaling, DNA damage and repair response (DDR) gene expression and translational control were all investigated. We show that platinum resistant OVCAR-3 ovarian cancer cells are re-sensitized to low levels of carboplatin in culture by mTOR inhibition, demonstrating reduced survival after treatment with either mTORC1 inhibitor everolimus or mTORC1/2 inhibitor PP242. Platinum resistance is shown to be associated with activating phosphorylation of AKT and CHK1, inactivating phosphorylation of 4E-BP1, the negative regulator of eIF4E, which promotes increased cap-dependent mRNA translation and increased levels of CHK1 and BRCA1 proteins. Animals with platinum resistant OVCAR-3 tumors treated with carboplatin plus mTORC1/2 inhibition had significantly longer median survival and strikingly reduced metastasis compared to animals treated with carboplatin plus everolimus which inhibits only mTORC1. Reduced tumor growth, metastasis and increased survival by mTORC1/2 inhibition with carboplatin treatment was associated with reduced AKT activating phosphorylation and increased 4E-BP1 hypo-phosphorylation (activation). We conclude that mTORC1/2 inhibition is superior to mTORC1 inhibition in reversing platinum resistance in tumors and strongly impairs AKT activation, DNA repair responses and translation, promoting improved survival in the background of platinum resistance.