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mTOR激酶抑制剂联合用药研究取得进展

  1. mTOR
  2. 抑制剂
  3. 激酶
  4. 用药
  5. 进展

来源:上海药物研究所 2014-04-24 23:07

mTOR信号通路是调控细胞生长与增殖的一个关键通路,并在多数人恶性肿瘤中高度激活,成为抗肿瘤药物研究和开发的热点。新一代mTOR激酶抑制剂由于它们能同时抑制mTORC1和mTORC2,在临床前研究中具有优于雷帕霉素的抗肿瘤活性。

mTOR信号通路是调控细胞生长与增殖的一个关键通路,并在多数人恶性肿瘤中高度激活,成为抗肿瘤药物研究和开发的热点。新一代mTOR激酶抑制剂由于它们能同时抑制mTORC1和mTORC2,在临床前研究中具有优于雷帕霉素的抗肿瘤活性。

中国科学院上海药物研究所丁健课题组建立了mTOR激酶抑制剂的发现和研究平台,在研究新mTOR抑制剂X-387的抗肿瘤作用机制(Biochem Pharmacol 2012;83:1183-94)同时,发现mTOR激酶抑制剂长时间作用后AKT活性能够恢复,同时导致一系列受体酪氨酸激酶受体表达上调,成为限制mTOR激酶抑制剂抗肿瘤活性的一个重要原因,而联合用药成为克服这一缺陷的重要策略。

乳腺癌已经成为我国女性最常见的恶性肿瘤,mTOR介导的信号通路以高频率在乳腺癌中高度激活,成为乳腺癌治疗的重要靶标。丁健课题组研究人员通过研究mTOR激酶抑制剂在多种不同基因背景的乳腺癌细胞中导致存活通路反馈性激活的机制,发现GFR, HER2,HER3和IRS-1的蛋白和mRNA水平在mTOR抑制后反馈性上升。分别下调上述蛋白表达后,在不同基因背景的乳腺癌细胞中不同程度地提高了mTOR抑制剂的增殖抑制活性。由于mTOR激酶抑制剂所引起的负反馈中多种关键蛋白是Hsp90的客户蛋白,mTOR激酶抑制剂与Hsp90抑制剂联合使用协同抑制多种不同背景的乳腺癌增殖。HSP90抑制剂通过下调多种受体酪氨酸激酶蛋白水平阻碍mTOR激酶抑制剂所引起PI3K/Akt的激活。研究同时发现,mTOR抑制剂能够阻止HSP90抑制剂导致的HSP70和HSP27的反馈性上调。mTOR抑制剂和HSP90抑制剂对于目前临床上难治的三阴性乳腺癌裸小鼠移植瘤也显示出显著的协同抗肿瘤活性。

以上研究表明mTOR激酶抑制剂与HSP90抑制剂协同抑制不同基因背景尤其是三阴性乳腺癌。以联合用药的手段优化以mTOR为靶点的抗肿瘤治疗不仅进一步阐明了mTOR抑制剂的作用模式,有利于靶向mTOR的抑制剂的进一步开发,并且对于mTOR激酶抑制剂和Hsp90抑制剂在乳腺癌中的临床应用具有指导意义。

该项研究结果近日发表于International Journal of Cancer, 上海药物所研究员丁健、蒙凌华为通讯作者。项目得到了国家自然科学基金委及新药创制重大专项资助。 (生物谷Bioon.com)

生物谷推荐的英文摘要:

International Journal of Cancer doi:10.1002/ijc.28880

HSP90 inhibitor AUY922 abrogates up-regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer

Si-Meng Chen?, Chen-Liang Guo?, Jia-Jie Shi, Yi-Chao Xu, Yi Chen, Yan-Yan Shen, Yi Su, Jian Ding andLing-Hua Meng*

mTOR inhibition led to activation of upstream receptor tyrosine kinases (RTKs) and AKT, which may attenuate the efficacy of mTOR kinase inhibitors. We sought to discover efficient drug combination with mTOR inhibitors by elucidating the survival feedback loops induced by mTOR inhibition in breast cancer. The feedback signaling upon treatment of mTOR inhibitor AZD8055 was determined and the combinatorial activity of AZD8055 and HSP90 inhibitor AUY922 in cell signaling and proliferation were detected. Treatment of breast cancer T47D cells with AZD8055 induced activation of AKT and phosphatidylinositol 3-kinase (PI3K), which was accompanied with increase in expression of multiple upstream proteins including EGFR, HER2, HER3 and IRS-1. Different RTKs were revealed to be responsible for the reactivation of AKT by AZD8055 in different breast cancer cell lines. Down-regulation of these proteins differentially enhanced the antiproliferative activity of AZD8055. AZD8055 and AUY922 displayed synergistic effect against a panel of human breast cancer cells irrespective their genotype, which was associated with enhanced cell cycle arrest and inhibition of DNA synthesis. AUY922 destabilized multiple tested tyrosine kinases and abrogated activation of AKT induced by AZD8055. AZD8055 also inhibited up-regulation of HSP70 and HSP27 upon AUY922 treatment. Cotreatment of these two drugs demonstrated synergistic activity against triple negative MDA-MB-468 xenograft without enhanced toxicity. The combination of AZD8055 and AUY922 demonstrated synergistic activity against various types of breast cancer and established a mechanistic rationale for a combination approach using catalytic mTOR kinase inhibitor and HSP90 inhibitor in the treatment of breast cancer.

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