酪氨酸激酶抑制剂（TKI）和mTOR抑制剂等靶向药物在提高肾癌患者生存期的同时也引发肿瘤细胞耐药性的出现。前期研究将PI3K/mTOR抑制剂BEZ235处理PTEN缺失的肾癌细胞786-O时发现随着处理时间的延长，PI3K下游p-AKT通路存在再激活效应，对肿瘤细胞的抑制作用减弱，信息学分析发现该效应可能是Aurora激酶A依赖性的，运用Aurora激酶A抑制剂MLN8237可逆转该效应并增强对PI3K通路的持续抑制作用。因此我们提出假说：PI3K/mTOR抑制剂BEZ235在处理PTEN突变的肾癌细胞时会发生p-AKT通路的再激活，可能是耐药原因之一；该效应发生需依赖Aurora激酶A，联合应用AURORA激酶A抑制剂MLN8237能够持续抑制PI3K通路，抑制肿瘤细胞的耐药抵抗。拟建立临床前模型研究在PTEN缺失且一线治疗失败的背景下，联用药物对肿瘤生长及耐药的影响及机制。

The targeted drugs for advanced metastatic renal cell carcinoma mainly include TKI and mTOR inhibitors. The emergence of these novel targeted therapies not only improves the survival time of patient’s but also followed with the resistance from the cancer cells. Our preliminary data show that the p-AKT pathway was re-activated at 2 weeks following the treatment of PI3K/mTOR inhibitor BEZ235 in 786-O RCC cell lines harboring PTEN loss mutation. Meanwhile, the inhibitory effect was diminished also which provides clues for the emergence of resistance. We speculate that this kind of effect was Aurora kinase A dependent, whose inhibitor MLN8237 could restore the inhibitory effect and strengthen the BEZ235 function. We establish our theory that the combined therapy for BEZ235 and MLN8237 could potentially strengthen the inhibition of PI3K/AKT/mTOR pathway. We plan to provide the robust evidence for next clinical study by establishing the preclinical model to study the inhibition and resistance of renal cell carcinoma following the treatment of combined therapy in the context of PTEN loss and first-line therapy Sunitinib failures.