Dual mTOR inhibitor MLN0128 suppresses Merkel cell carcinoma (MCC) xenograft tumor growth.
Dual mTOR inhibitor MLN0128 suppresses Merkel cell carcinoma (MCC) xenograft tumor growth.
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DOI：
10.18632/oncotarget.5878
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发表时间：
2016-02-09
期刊：
影响因子：
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通讯作者：
Gao L
中科院分区：
文献类型：
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作者：
Kannan A;Lin Z;Shao Q;Zhao S;Fang B;Moreno MA;Vural E;Stack BC Jr;Suen JY;Kannan K;Gao L
默克尔细胞癌(MCC)是一种侵袭性神经内分泌皮肤癌。MCC常表现为PI3K/mTOR通路的病理性激活和c-Myc的高表达。然而，目前还没有针对这种致命疾病的靶向治疗方法。最近，第二代双TORC1/2抑制剂MLN0128在临床前研究中被证明具有治疗效果。MLN0128目前正在进行临床试验，作为一种治疗晚期癌症的潜在疗法。在这里，我们描述了MLN0128在MCC临床前环境中的治疗效果，并描绘了MCC细胞系统中mTORC1/2的下游靶点。MLN0128显著抑制不依赖于Merkel细胞多瘤病毒的异种移植MCC肿瘤生长。此外，MLN0128还能显著抑制MCC细胞的增殖并诱导其凋亡。进一步的研究表明，衰老并不参与MLN0128介导的抑制移植瘤MCC生长的作用。最后，我们还观察到当MLN0128与溴域蛋白BRD4抑制剂JQ1联合治疗时，具有强大的抗肿瘤作用。提示双重阻断PI3K/mTOR通路和c-Myc轴可有效抑制MCC的生长。我们的结果表明，MLN0128作为单一疗法或作为JQ1与JQ1联合治疗晚期MCC的成员是有效的。
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. Pathologic activation of PI3K/mTOR pathway and elevated expression of c-Myc are frequently detected in MCC. Yet, there is no targeted therapy presently available for this lethal disease. Recently, MLN0128, a second-generation dual TORC1/2 inhibitor is shown to have therapeutic efficacy in preclinical studies. MLN0128 is currently in clinical trials as a potential therapy for advanced cancers. Here we characterize the therapeutic efficacy of MLN0128 in the preclinical setting of MCC and delineate downstream targets of mTORC1/2 in MCC cellular systems. MLN0128 significantly attenuates xenograft MCC tumor growth independent of Merkel cell polyomavirus. Moreover, MLN0128 markedly diminishes MCC cell proliferation and induces apoptosis. Further investigations indicate that senescence does not contribute to MLN0128-mediated repression of xenograft MCC tumor growth. Finally, we also observe robust antitumor effects of MLN0128 when administered as a dual therapy with JQ1, a bromodomain protein BRD4 inhibitor. These results suggest dual blockade of PI3K/mTOR pathway and c-Myc axis is effective in the control of MCC tumor growth. Our results demonstrate that MLN0128 is potent as monotherapy or as a member of combination therapy with JQ1 for advanced MCC.