title: Dual mTOR inhibitor MLN0128 suppresses Merkel cell carcinoma (MCC) xenograft tumor growth.
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.
authors.affiliation: Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Aarthi
authors.initials: A
authors.lastname: Kannan
authors.affiliation: Current address: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Current address: Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shao
authors.affiliation: Pulaski Academy, Little Rock, AR 72212, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Fang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Mauricio A
authors.initials: MA
authors.lastname: Moreno
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Emre
authors.initials: E
authors.lastname: Vural
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Brendan C
authors.initials: BC
authors.lastname: Stack
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: James Y
authors.initials: JY
authors.lastname: Suen
authors.affiliation: Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.|Current address: Biomolecular Integrations, Little Rock, AR 72207, USA.
authors.forename: Krishnaswamy
authors.initials: K
authors.lastname: Kannan
authors.affiliation: Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001381:Azepines / Q000494:pharmacology; D001583:Benzoxazoles / Q000494:pharmacology*; D015153:Blotting, Western; D015266:Carcinoma, Merkel Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects*; D016922:Cellular Senescence; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D001381:Azepines; D001583:Benzoxazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; D014230:Triazoles; C561695:(+)-JQ1 compound; C546842:MTOR protein, human; C572449:sapanisertib; D000225:Adenine
keywords: MLN0128; Merkel cell carcinoma; mTOR inhibitor; mTOR pathway