mTOR激酶抑制劑聯合用藥研究取得進展

mTOR信號通路是調控細胞生長與增殖的一個關鍵通路，並在多數人惡性腫瘤中高度激活，成為抗腫瘤藥物研究和開發的熱點。新一代mTOR激酶抑制劑由於它們能同時抑制mTORC1和mTORC2，在臨床前研究中具有優於雷帕黴素的抗腫瘤活性。

中國科學院上海藥物研究所丁健課題組建立了mTOR激酶抑制劑的發現和研究平臺，在研究新mTOR抑制劑X-387的抗腫瘤作用機制（Biochem Pharmacol 2012；83：1183-94）同時，發現mTOR激酶抑制劑長時間作用後AKT活性能夠恢復，同時導致一系列受體酪氨酸激酶受體表達上調，成為限制mTOR激酶抑制劑抗腫瘤活性的一個重要原因，而聯合用藥成為克服這一缺陷的重要策略。

乳腺癌已經成為我國女性最常見的惡性腫瘤，mTOR介導的信號通路以高頻率在乳腺癌中高度激活，成為乳腺癌治療的重要靶標。丁健課題組研究人員通過研究mTOR激酶抑制劑在多種不同基因背景的乳腺癌細胞中導致存活通路反饋性激活的機制，發現GFR， HER2，HER3和IRS-1的蛋白和mRNA水平在mTOR抑制後反饋性上升。分別下調上述蛋白表達後，在不同基因背景的乳腺癌細胞中不同程度地提高了mTOR抑制劑的增殖抑制活性。由於mTOR激酶抑制劑所引起的負反饋中多種關鍵蛋白是Hsp90的客戶蛋白，mTOR激酶抑制劑與Hsp90抑制劑聯合使用協同抑制多種不同背景的乳腺癌增殖。HSP90抑制劑通過下調多種受體酪氨酸激酶蛋白水平阻礙mTOR激酶抑制劑所引起PI3K/Akt的激活。研究同時發現，mTOR抑制劑能夠阻止HSP90抑制劑導致的HSP70和HSP27的反饋性上調。mTOR抑制劑和HSP90抑制劑對於目前臨床上難治的三陰性乳腺癌裸小鼠移植瘤也顯示出顯著的協同抗腫瘤活性。

以上研究表明mTOR激酶抑制劑與HSP90抑制劑協同抑制不同基因背景尤其是三陰性乳腺癌。以聯合用藥的手段優化以mTOR為靶點的抗腫瘤治療不僅進一步闡明了mTOR抑制劑的作用模式，有利於靶向mTOR的抑制劑的進一步開發，並且對於mTOR激酶抑制劑和Hsp90抑制劑在乳腺癌中的臨床應用具有指導意義。

該項研究結果近日發表於International Journal of Cancer， 上海藥物所研究員丁健、蒙凌華為通訊作者。項目得到了國家自然科學基金委及新藥創製重大專項資助。 （生物谷Bioon.com）

生物谷推薦的英文摘要：

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.