title: Carfilzomib is an effective anticancer agent in anaplastic thyroid cancer.
abstract: Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies. Currently, there is no standard or effective therapy for ATC. Drug repurposing for cancer treatment is an emerging approach for identifying compounds that may have antineoplastic effects. The aim of this study was to use high-throughput drug library screening to identify and subsequently validate novel therapeutic agents with anticancer effects in ATC. We performed quantitative high-throughput screening (qHTS) in ATC cell lines (SW-1736, 8505C, and C-643), using a compound library of 3282 drugs. qHTS identified 100 compounds that were active in all three ATC cell lines. Proteasome inhibitors were one of the most active drug categories according to enrichment analysis. Of the three proteasome inhibitors screened, a second-generation proteasome inhibitor, carfilzomib, was the most active. Treatment of ATC cells with carfilzomib significantly inhibited cellular proliferation and induced G2/M cell cycle arrest and caspase-dependent apoptosis. Mechanistically, carfilzomib increased expression of p27 (CDKN1B) and decreased expression of the anti-apoptotic protein ATF4. Pretreatment with carfilzomib reduced in vivo metastases (lung, bone, liver, and kidney) and disease progression, and decreased N-cadherin expression. Carfilzomib treatment of mice with established, widely metastatic disease significantly increased their survival, without significant toxicity. Our findings support the use or clinical study of carfilzomib as a therapeutic option in patients with advanced and metastatic ATC.
authors.affiliation: Endocrine Oncology BranchNational Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USAGeisel School of Medicine at DartmouthHanover, New Hampshire 03755, USANational Institutes of HealthNational Center for Advancing Translational Sciences, Bethesda, Maryland, USA Endocrine Oncology BranchNational Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USAGeisel School of Medicine at DartmouthHanover, New Hampshire 03755, USANational Institutes of HealthNational Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Endocrine Oncology BranchNational Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USAGeisel School of Medicine at DartmouthHanover, New Hampshire 03755, USANational Institutes of HealthNational Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Endocrine Oncology BranchNational Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USAGeisel School of Medicine at DartmouthHanover, New Hampshire 03755, USANational Institutes of HealthNational Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
authors.forename: Myriem
authors.initials: M
authors.lastname: Boufraqech
authors.affiliation: Endocrine Oncology BranchNational Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USAGeisel School of Medicine at DartmouthHanover, New Hampshire 03755, USANational Institutes of HealthNational Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Endocrine Oncology BranchNational Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USAGeisel School of Medicine at DartmouthHanover, New Hampshire 03755, USANational Institutes of HealthNational Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
authors.forename: Dhaval
authors.initials: D
authors.lastname: Patel
authors.affiliation: Endocrine Oncology BranchNational Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USAGeisel School of Medicine at DartmouthHanover, New Hampshire 03755, USANational Institutes of HealthNational Center for Advancing Translational Sciences, Bethesda, Maryland, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.affiliation: Endocrine Oncology BranchNational Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USAGeisel School of Medicine at DartmouthHanover, New Hampshire 03755, USANational Institutes of HealthNational Center for Advancing Translational Sciences, Bethesda, Maryland, USA kebebewe@mail.nih.gov.
authors.forename: Electron
authors.initials: E
authors.lastname: Kebebew
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D009842:Oligopeptides / Q000494:pharmacology*; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; C524865:carfilzomib
keywords: anaplastic thyroid cancer; carfilzomib; high-throughput screening; proteasome inhibitor