Dual modulation of MCL-1 and mTOR determines the response to sunitinib
Dual modulation of MCL-1 and mTOR determines the response to sunitinib
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DOI：
10.1172/jci84386
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发表时间：
2017-01-03
影响因子：
15.9
通讯作者：
Minucci, Saverio
中科院分区：
文献类型：
--
作者：
Elgendy, Mohamed;Abdel-Aziz, Amal Kamal;Minucci, Saverio
大多数患者最初对多酪氨酸激酶抑制剂舒尼替尼的治疗有反应，最终复发。因此，深入了解舒尼替尼的众多靶点对临床反应或耐药性的贡献是至关重要的。在这里，我们已经证明，癌细胞对临床相关剂量的舒尼替尼的反应是通过增强抗凋亡蛋白MCL-1的稳定性和诱导mTORC1信号转导，因此引起的细胞毒性很小。抑制mCL-1或mTORC1信号在体外使细胞对临床相关剂量的舒尼替尼敏感，并与舒尼替尼在体内协同抑制肿瘤生长，表明这些反应是作为生存机制被触发的，使细胞能够耐受舒尼替尼的细胞毒作用。此外，较高剂量的舒尼替尼具有细胞毒性，引发mCL-1水平下降，并抑制mTORC1信号转导。从机制上讲，我们确定舒尼替尼通过影响蛋白酶体的降解来调节MCL-1的稳定性。不同剂量范围的舒尼替尼对mCL-1稳定性的双重调节是由于对ERK和GSK3β活性的不同影响，后者也解释了mTORC1活性的双重调节。最后，对舒尼替尼治疗前后患者样本的比较表明，mCL-1水平和mTORC1活性的增加与患者对舒尼替尼的耐药性有关。
Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3 beta activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients.