Oncotarget

Research Papers:

Dual mTOR inhibitor MLN0128 suppresses Merkel cell carcinoma (MCC) xenograft tumor growth

Aarthi Kannan, Zhenyu Lin, Qiang Shao, Stephanie Zhao, Bin Fang, Mauricio A. Moreno, Emre Vural, Brendan C. Stack, Jr., James Y. Suen, Krishnaswamy Kannan and Ling Gao _

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Oncotarget. 2016; 7:6576-6592. https://doi.org/10.18632/oncotarget.5878

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Abstract

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

Correspondence to:

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

ABSTRACT

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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