title: Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma.
abstract: OBJECTIVE
  Oncogenic fusions consisting of fibroblast growth factor receptor (FGFR) and TACC are present in a subgroup of glioblastoma (GBM) and other human cancers and have been proposed as new therapeutic targets. We analyzed frequency and molecular features of FGFR-TACC fusions and explored the therapeutic efficacy of inhibiting FGFR kinase in GBM and grade II and III glioma.
  
  
  METHODS
  Overall, 795 gliomas (584 GBM, 85 grades II and III with wild-type and 126 with IDH1/2 mutation) were screened for FGFR-TACC breakpoints and associated molecular profile. We also analyzed expression of the FGFR3 and TACC3 components of the fusions. The effects of the specific FGFR inhibitor JNJ-42756493 for FGFR3-TACC3-positive glioma were determined in preclinical experiments. Two patients with advanced FGFR3-TACC3-positive GBM received JNJ-42756493 and were assessed for therapeutic response.
  
  
  RESULTS
  Three of 85 IDH1/2 wild-type (3.5%) but none of 126 IDH1/2-mutant grade II and III gliomas harbored FGFR3-TACC3 fusions. FGFR-TACC rearrangements were present in 17 of 584 GBM (2.9%). FGFR3-TACC3 fusions were associated with strong and homogeneous FGFR3 immunostaining. They are mutually exclusive with IDH1/2 mutations and EGFR amplification, whereas they co-occur with CDK4 amplification. JNJ-42756493 inhibited growth of glioma cells harboring FGFR3-TACC3 in vitro and in vivo. The two patients with FGFR3-TACC3 rearrangements who received JNJ-42756493 manifested clinical improvement with stable disease and minor response, respectively.
  
  
  CONCLUSIONS
  RT-PCR sequencing is a sensitive and specific method to identify FGFR-TACC-positive patients. FGFR3-TACC3 fusions are associated with uniform intratumor expression of the fusion protein. The clinical response observed in the FGFR3-TACC3-positive patients treated with an FGFR inhibitor supports clinical studies of FGFR inhibition in FGFR-TACC-positive patients.
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, Paris, France. AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris, France. Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
authors.forename: Anna Luisa
authors.initials: AL
authors.lastname: Di Stefano
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, New York.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fucci
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, New York.
authors.forename: Veronique
authors.initials: V
authors.lastname: Frattini
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, Paris, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Labussiere
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, Paris, France. AP-HP, Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle, Paris, France. AP-HP Onconeurothèque, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Karima
authors.initials: K
authors.lastname: Mokhtari
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, New York.
authors.forename: Pietro
authors.initials: P
authors.lastname: Zoppoli
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, Paris, France. Institut du Cerveau et de la Moelle épinière (ICM), Plateforme de Génotypage Séquençage, Paris, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Marie
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, Paris, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Bruno
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, Paris, France.
authors.forename: Blandine
authors.initials: B
authors.lastname: Boisselier
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Giry
authors.affiliation: Fondation Ophtalmologique A. de Rothschild, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Savatovsky
authors.affiliation: Drug Development Department, Gustave Roussy Cancer Center, Paris, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Touat
authors.affiliation: AP-HP, Groupe Hospitalier Pitié Salpêtrière, Department of Neurosurgery, Paris, France.
authors.forename: Hayat
authors.initials: H
authors.lastname: Belaid
authors.affiliation: Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Kamoun
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, Paris, France. AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Idbaih
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Houillier
authors.affiliation: Janssen Pharmaceutical Companies of Johnson and Johnson, Titusville, New Jersey.
authors.forename: Feng R
authors.initials: FR
authors.lastname: Luo
authors.affiliation: Drug Development Department, Gustave Roussy Cancer Center, Paris, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Fondazione I.R.C.C.S Istituto Neurologico C. Besta, Milan, Italy.
authors.forename: Marica
authors.initials: M
authors.lastname: Eoli
authors.affiliation: Fondazione I.R.C.C.S Istituto Neurologico C. Besta, Milan, Italy.
authors.forename: Rosina
authors.initials: R
authors.lastname: Paterra
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Yip
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Petrecca
authors.affiliation: University of Calgary, Calgary, Canada.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.affiliation: Fondazione I.R.C.C.S Istituto Neurologico C. Besta, Milan, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Finocchiaro
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, New York. Department of Pediatrics and Pathology, Columbia University Medical Center, New York, New York.
authors.forename: Anna
authors.initials: A
authors.lastname: Lasorella
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, Paris, France. AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris, France. AP-HP Onconeurothèque, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. marc.sanson@psl.aphp.fr ai2102@columbia.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Sanson
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, New York. Department of Neurology and Pathology, Columbia University Medical Center, New York, New York. marc.sanson@psl.aphp.fr ai2102@columbia.edu.
authors.forename: Antonio
authors.initials: A
authors.lastname: Iavarone
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics; D058990:Molecular Targeted Therapy; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011720:Pyrazoles / Q000627:therapeutic use*; D011810:Quinoxalines / Q000627:therapeutic use*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; D011720:Pyrazoles; D011810:Quinoxalines; C120551:TACC3 protein, human; C000604580:erdafitinib; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3