title: Torin2 targets dysregulated pathways in anaplastic thyroid cancer and inhibits tumor growth and metastasis.
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.
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Samira M
authors.initials: SM
authors.lastname: Sadowski
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Myriem
authors.initials: M
authors.lastname: Boufraqech
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.affiliation: Division of Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Zhuyin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Division of Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Electron
authors.initials: E
authors.lastname: Kebebew
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D016688:Mice, Inbred NOD; D058990:Molecular Targeted Therapy; D009287:Naphthyridines / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: C558529:9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; C488158:CLSPN protein, human; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009287:Naphthyridines; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D000077022:Survivin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020169:Caspases
keywords: Torin2; anaplastic thyroid cancer; mTOR; mTORC1 inhibitor; quantitative high-troughput screening