Dataset Information

Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma.

ABSTRACT: PURPOSE: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. EXPERIMENTAL DESIGN: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.

SUBMITTER: Di Stefano AL

PROVIDER: S-EPMC4506218 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma.

Di Stefano Anna Luisa AL Fucci Alessandra A Frattini Veronique V Labussiere Marianne M Mokhtari Karima K Zoppoli Pietro P Marie Yannick Y Bruno Aurelie A Boisselier Blandine B Giry Marine M Savatovsky Julien J Touat Mehdi M Belaid Hayat H Kamoun Aurelie A Idbaih Ahmed A Houillier Caroline C Luo Feng R FR Soria Jean-Charles JC Tabernero Josep J Eoli Marica M Paterra Rosina R Yip Stephen S Petrecca Kevin K Chan Jennifer A JA Finocchiaro Gaetano G Lasorella Anna A Sanson Marc M Iavarone Antonio A

Clinical cancer research : an official journal of the American Association for Cancer Research 20150121 14

<h4>Purpose</h4>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.<h4>Experimental design</h4>Overall, 795 gliomas (584 GBM, 85 grades II and III with wild-type and 126 with IDH1/2 ...[more]

PMID: 25609060

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Dataset Information

Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma.

Publications

Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma.

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