Dual mTOR inhibitor MLN0128 suppresses Merkel cell carcinoma (MCC) xenograft tumor growth
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Aarthi Kannan1, Zhenyu Lin4, Qiang Shao5, Stephanie Zhao6, Bin Fang1, Mauricio A. Moreno2, Emre Vural2, Brendan C. Stack Jr2, James Y. Suen2, Krishnaswamy Kannan3,7, Ling Gao1
1Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
2Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
3Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
4Current address: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
5Current address: Critical Care Medicine, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
6Pulaski Academy, Little Rock, AR 72212, USA
7Current address: Biomolecular Integrations, Little Rock, AR 72207, USA
Ling Gao, e-mail: LGao@uams.edu
Keywords: Merkel cell carcinoma, mTOR pathway, mTOR inhibitor, MLN0128
Received: June 04, 2015 Accepted: October 13, 2015 Published: October 23, 2015
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.
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