Potential role of mTORC2 as a therapeutic target in clear cell carcinoma of the ovary.
Potential role of mTORC2 as a therapeutic target in clear cell carcinoma of the ovary.
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DOI：
10.1158/1535-7163.mct-12-1185
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发表时间：
2013-07
影响因子：
5.7
通讯作者：
Kimura T
中科院分区：
文献类型：
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作者：
Hisamatsu T;Mabuchi S;Matsumoto Y;Kawano M;Sasano T;Takahashi R;Sawada K;Ito K;Kurachi H;Schilder RJ;Testa JR;Kimura T
本研究的目的是研究mTORC 2作为卵巢透明细胞癌（CCC）治疗靶点的作用，CCC被认为是一种侵袭性、化疗耐药的组织学亚型。使用98例原发性卵巢癌（52例CCC和46例浆液性腺癌（SAC））的组织微阵列，通过免疫组织化学评估mTORC 2的激活。然后，使用两对RAD 001敏感的亲本（RMG 2和HAC 2）和RAD 001抗性CCC细胞系（RMG 2-RR和HAC 2-RR）检查mTORC 2靶向治疗的生长抑制作用，以及mTORC 2信号传导作为卵巢CCC中对mTORC 1抑制剂RAD 001获得性抗性的机制的作用。mTORC 2在CCC中的激活频率高于SAC（71.2% vs. 45.7%）。AZD 8055同时抑制mTORC 1和mTORC 2可显著抑制体外培养的RAD 001敏感细胞和RAD 001耐药细胞的增殖。在RAD 001敏感的CCC细胞中，用RAD 001处理诱导mTORC 2介导的AKT活化。此外，与相应的亲本细胞相比，在RAD 001抗性CCC细胞中观察到mTORC 2-AKT信号传导的活化增加。在RAD 001处理期间抑制mTORC 2增强了RAD 001的抗肿瘤作用，并防止CCC细胞获得对RAD 001的抗性。总之，mTORC 2在卵巢CCCs中经常被激活，并且可以成为有希望的治疗靶点。此外，mTORC 2靶向治疗可能在一线环境中以及在RAD 001治疗后发生的复发性疾病的二线治疗中有效。
The goal of this study was to examine the role of mTORC2 as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histological subtype. Using tissue microarrays of 98 primary ovarian cancers (52 CCCs and 46 serous adenocarcinomas (SACs)), activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTORC1 inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR). mTORC2 was more frequently activated in CCCs than in SACs (71.2% vs. 45.7%). Simultaneous inhibition of mTORC1 and mTORC2 by AZD8055 markedly inhibited the proliferation of both RAD001-sensitive and RAD001-resistant cells in vitro. Treatment with RAD001 induced mTORC2-mediated AKT activation in RAD001-sensitive CCC cells. Moreover, increased activation of mTORC2-AKT signaling was observed in RAD001-resistant CCC cells compared to the respective parental cells. Inhibition of mTORC2 during RAD001 treatment enhanced the anti-tumor effect of RAD001 and prevented CCC cells from acquiring resistance to RAD001. In conclusion, mTORC2 is frequently activated, and can be a promising therapeutic target, in ovarian CCCs. Moreover, mTORC2-targeted therapy may be efficacious in a front-line setting as well as for second-line treatment of recurrent disease developing after RAD001-treatment.