Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma.
Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma.
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DOI：
10.1158/1078-0432.ccr-14-2199
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发表时间：
2015-07-15
期刊：
影响因子：
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通讯作者：
Iavarone A
中科院分区：
文献类型：
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作者：
Di Stefano AL;Fucci A;Frattini V;Labussiere M;Mokhtari K;Zoppoli P;Marie Y;Bruno A;Boisselier B;Giry M;Savatovsky J;Touat M;Belaid H;Kamoun A;Idbaih A;Houillier C;Luo FR;Soria JC;Tabernero J;Eoli M;Paterra R;Yip S;Petrecca K;Chan JA;Finocchiaro G;Lasorella A;Sanson M;Iavarone A
Oncogenic fusions consisting of 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, molecular features of FGFR-TACC fusions, and explored the therapeutic efficacy of inhibiting FGFR kinase in GBM and grade-II–III glioma. Overall, 795 gliomas (584 GBM, 85 grade-II–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. Three of 85 IDH1/2 wild type (3.5%) but none of 126 IDH1/2 mutant grade-II–III glioma 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 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. RT-PCR-sequencing is a sensitive and specific method to identify FGFR-TACC-positive patients. FGFR3-TACC3 fusions are associated with uniform intra-tumor expression of the fusion protein. The clinical response observed in the FGFR3-TACC3-positive patients treated with a FGFR inhibitor supports clinical studies of FGFR inhibition in FGFR-TACC-positive patients.
