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Torin2 targets dysregulated pathways in anaplastic thyroid cancer and inhibits tumor growth and metastasis

2015; Impact Journals LLC; Volume: 6; Issue: 20 Linguagem: Inglês

10.18632/oncotarget.3833

1949-2553

Samira M. Sadowski, Myriem Boufraqech, Lisa Zhang, Amit Mehta, Payal Kapur, Yaqin Zhang, Zhuyin Li, Min Shen, Electron Kebebew,

Cancer-related Molecular Pathways

// Samira M. Sadowski 1 , Myriem Boufraqech 1 , Lisa Zhang 1 , Amit Mehta 2 , Payal Kapur 3 , Yaqin Zhang 4 , Zhuyin Li 4 , Min Shen 4 and Electron Kebebew 1 1 Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 2 Geisel School of Medicine at Dartmouth, Hanover, NH, USA 3 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA 4 Division of Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA Correspondence to: Samira M. Sadowski, email: // Keywords : torin2, mTORC1 inhibitor, mTOR, anaplastic thyroid cancer, quantitative high-troughput screening Received : February 20, 2015 Accepted : March 26, 2015 Published : April 14, 2015 Abstract Anaplastic thyroid cancer (ATC) is rare but it is one of the most lethal human malignancies with no effective therapy. There is a pressing need to identify new therapeutic agents for ATC. We performed quantitative high-throughput screening (qHTS) in ATC cell lines using a compound library of 3,282 drugs. qHTS identified 100 pan-active agents. Enrichment analysis of qHTS data showed drugs targeting mTOR were one of the most active drug categories, and Torin2 showed the highest efficacy. We found mTOR to be upregulated in ATC. Treatment of multiple ATC cell lines with Torin2 showed significant dose-dependent inhibition of cellular proliferation with caspase-dependent apoptosis and G1/S phase arrest. Torin2 inhibited cellular migration and inhibited the phosphorylation of key effectors of the mTOR-pathway (AKT, 4E-BP1 and 70S6K), as well as claspin and survivin expression, regulators of cell cycle and apoptosis. In our in vivo mouse model of metastatic ATC, Torin2 inhibited tumor growth and metastasis and significantly prolonged overall survival. Our findings suggest that Torin2 is a promising agent for ATC therapy and that it effectively targets upregulated pathways in human ATC.