title: Response and acquired resistance to everolimus in anaplastic thyroid cancer.
abstract: Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors.
authors.affiliation: From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School (N.W., E.M.V.A., N.G., R.I.H., D.J.K., P.A.J., L.A.G., J.H.L.), the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (N.W., E.M.V.A., Y.G., R.I.H., D.J.K., P.A.J., L.A.G., J.H.L.), the Departments of Pathology (J.A.B.) and Surgery (S.J.S., D.T.R.), Brigham and Women's Hospital, the Department of Medicine, Beth Israel Deaconess Medical Center (G.J.H.), and Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute (P.A.J.) - all in Boston; and Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard (N.W., E.M.V.A., A.A.-M., A.T.-W., M.R., G.G., D.J.K., S.L.C., D.M.S., L.A.G.), Whitehead Institute for Biomedical Research and the MIT Department of Biology (B.C.G., D.M.S.), and Howard Hughes Medical Institute, MIT (B.C.G., D.M.S.) - all in Cambridge, MA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Wagle
authors.forename: Brian C
authors.initials: BC
authors.lastname: Grabiner
authors.forename: Eliezer M
authors.initials: EM
authors.lastname: Van Allen
authors.forename: Ali
authors.initials: A
authors.lastname: Amin-Mansour
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.forename: Mara
authors.initials: M
authors.lastname: Rosenberg
authors.forename: Nathanael
authors.initials: N
authors.lastname: Gray
authors.forename: Justine A
authors.initials: JA
authors.lastname: Barletta
authors.forename: Yanan
authors.initials: Y
authors.lastname: Guo
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Swanson
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Ruan
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Hanna
authors.forename: Robert I
authors.initials: RI
authors.lastname: Haddad
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Lorch
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000068338:Everolimus; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging / Q000473:pathology; D011487:Protein Conformation; D011859:Radiography; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics*; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus