Modulation of Akt/mTOR signaling overcomes sunitinib resistance in renal and prostate cancer cells.
Modulation of Akt/mTOR signaling overcomes sunitinib resistance in renal and prostate cancer cells.
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DOI：
10.1158/1535-7163.mct-11-0907
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发表时间：
2012-07
影响因子：
5.7
通讯作者：
Kolenko VM
中科院分区：
文献类型：
--
作者：
Makhov PB;Golovine K;Kutikov A;Teper E;Canter DJ;Simhan J;Uzzo RG;Kolenko VM
酪氨酸激酶抑制剂（TKI）对晚期肾细胞癌表现出令人印象深刻的活性。然而，最近的临床研究表明，去势抵抗性前列腺癌患者对舒尼替尼的反应不确定。肿瘤抑制性磷酸酶和张力蛋白同源物（PTEN）充当PI 3 K/Akt/mTOR细胞存活途径的看门人。我们的实验表明，在肾和前列腺癌细胞中，PTEN表达与舒尼替尼耐药呈负相关。在体外和体内，PTEN表达的恢复显著增加肿瘤细胞对舒尼替尼的敏感性。此外，用PI 3 K/mTOR抑制剂GDC-0980、mTOR抑制剂替西罗莫司或泛Akt抑制剂GSK 690693对PI 3 K/Akt/mTOR信号传导进行药理学操纵能够克服癌细胞中的舒尼替尼抗性。我们的研究结果强调了PTEN表达与舒尼替尼耐药相关的重要性，并暗示了舒尼替尼除了其抗血管生成作用外，还对肿瘤细胞具有直接的细胞毒性作用。
Tyrosine kinase inhibitors (TKIs) exhibit impressive activity against advanced renal cell carcinoma. However, recent clinical studies have demonstrated an equivocal response to sunitinib in patients with castration-resistant prostate cancer. The tumor suppressor phosphatase and tensin homolog (PTEN) acts as a gatekeeper of the PI3K/Akt/mTOR cell-survival pathway. Our experiments demonstrate that PTEN expression inversely correlates with sunitinib resistance in renal and prostate cancer cells. Restoration of PTEN expression markedly increases sensitivity of tumor cells to sunitinib both in vitro and in vivo. In addition, pharmacologic manipulation of PI3K/Akt/mTOR signaling with PI3K/mTOR inhibitor, GDC-0980, mTOR inhibitor, temsirolimus, or pan-Akt inhibitor, GSK690693, was able to overcome sunitinib resistance in cancer cells. Our findings underscore the importance of PTEN expression in relation to sunitinib resistance and imply a direct cytotoxic effect by sunitinib on tumor cells in addition to its anti-angiogenic actions.