title: Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib.
abstract: Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole-exome sequencing of a patient with a 14-month complete response on this trial revealed two concurrent mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biologic mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or "personalized") medicine approaches to screen patients with cancer for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.
authors.affiliation: Departments of 1Medical Oncology and 2Biostatistics and Computational Biology, 3Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute; Departments of 4Medicine and 5Pathology, Brigham and Women's Hospital, Harvard Medical School; 6Division of Hematology/Oncology, Massachusetts General Hospital, Boston; 7Broad Institute of Harvard and MIT; 8Department of Biology, Whitehead Institute for Biomedical Research; 9Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts; and 10Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
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: Eran
authors.initials: E
authors.lastname: Hodis
authors.forename: Susanna
authors.initials: S
authors.lastname: Jacobus
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.forename: Michelle
authors.initials: M
authors.lastname: Stewart
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.forename: Leena
authors.initials: L
authors.lastname: Gandhi
authors.forename: James M
authors.initials: JM
authors.lastname: Cleary
authors.forename: Aymen A
authors.initials: AA
authors.lastname: Elfiky
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Taplin
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stack
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000235:genetics; D004334:Drug Administration Schedule; D000068338:Everolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007191:Indazoles; D008207:Lymphatic Metastasis / Q000000981:diagnostic imaging / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D057285:Precision Medicine; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011877:Radionuclide Imaging; D017422:Sequence Analysis, DNA; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases