title: Genomic Heterogeneity and Exceptional Response to Dual Pathway Inhibition in Anaplastic Thyroid Cancer.
abstract: Purpose:Cancers may resist single-agent targeted therapies when the flux of cellular growth signals is shifted from one pathway to another. Blockade of multiple pathways may be necessary for effective inhibition of tumor growth. We document a case in which a patient with anaplastic thyroid carcinoma (ATC) failed to respond to either mTOR/PI3K or combined RAF/MEK inhibition but experienced a dramatic response when both drug regimens were combined.Experimental Design:Multi-region whole-exome sequencing of five diagnostic and four autopsy tumor biopsies was performed. Meta-analysis of DNA and RNA sequencing studies of ATC was performed.Results:Sequencing revealed truncal BRAF and PIK3CA mutations, which are known to activate the MAPK and PI3K/AKT pathways, respectively. Meta-analysis demonstrated 10.3% cooccurrence of MAPK and PI3K pathway alterations in ATC. These tumors display a separate transcriptional profile from other ATCs, consistent with a novel subgroup of ATC.Conclusions:BRAF and PIK3CA mutations define a distinct subset of ATC. Blockade of the MAPK and PI3K pathways appears necessary for tumor response in this subset of ATC. This identification of synergistic activity between targeted agents may inform clinical trial design in ATC.Clin Cancer Res; 23(9); 2367-73. ©2016 AACR.
authors: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|The Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts.
authors: William J
authors: WJ
authors: Gibson
authors: Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Daniel T
authors: DT
authors: Ruan
authors: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Vera A
authors: VA
authors: Paulson
authors: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Justine A
authors: JA
authors: Barletta
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Glenn J
authors: GJ
authors: Hanna
authors: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors: Stefan
authors: S
authors: Kraft
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Antonio
authors: A
authors: Calles
authors: Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Matthew A
authors: MA
authors: Nehs
authors: Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Francis D
authors: FD
authors: Moore
authors: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors: Amaro
authors: A
authors: Taylor-Weiner
authors: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|The Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts.
authors: Jeremiah A
authors: JA
authors: Wala
authors: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|The Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts.
authors: Travis I
authors: TI
authors: Zack
authors: Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Thomas C
authors: TC
authors: Lee
authors: Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Fiona M
authors: FM
authors: Fennessy
authors: Department of Endocrinology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Erik K
authors: EK
authors: Alexander
authors: Department of Otolaryngology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Tom
authors: T
authors: Thomas
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Pasi A
authors: PA
authors: Janne
authors: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Broad Institute, Boston, Massachusetts.
authors: Levi A
authors: LA
authors: Garraway
authors: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.|Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Broad Institute, Boston, Massachusetts.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Chan School of Public Health, Boston, Massachusetts.
authors: Scott L
authors: SL
authors: Carter
authors: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Broad Institute, Boston, Massachusetts.
authors: Rameen
authors: R
authors: Beroukhim
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. eliezerm_vanallen@dfci.harvard.edu Jochen_Lorch@dfci.harvard.edu.
authors: Jochen H
authors: JH
authors: Lorch
authors: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts. eliezerm_vanallen@dfci.harvard.edu Jochen_Lorch@dfci.harvard.edu.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Broad Institute, Boston, Massachusetts.
authors: Eliezer M
authors: EM
authors: Van Allen
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D018740:Genetic Heterogeneity / Q000187:drug effects; D023281:Genomics; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000073359:Exome Sequencing; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D020930:MAP Kinase Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D048490:raf Kinases; C546842:MTOR protein, human; C482119:BRAF protein, human