Di Stefano Anna Luisa, Fucci Alessandra, Frattini Veronique, Labussiere Marianne, Mokhtari Karima, Zoppoli Pietro, Marie Yannick, Bruno Aurelie, Boisselier Blandine, Giry Marine, Savatovsky Julien, Touat Mehdi, Belaid Hayat, Kamoun Aurelie, Idbaih Ahmed, Houillier Caroline, Luo Feng R, Soria Jean-Charles, Tabernero Josep, Eoli Marica, Paterra Rosina, Yip Stephen, Petrecca Kevin, Chan Jennifer A, Finocchiaro Gaetano, Lasorella Anna, Sanson Marc, Iavarone Antonio
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.
Institute for Cancer Genetics, Columbia University Medical Center, New York, New York.
Clin Cancer Res. 2015 Jul 15;21(14):3307-17. doi: 10.1158/1078-0432.CCR-14-2199. Epub 2015 Jan 21.
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.
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.
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.
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.
由成纤维细胞生长因子受体（FGFR）和TACC组成的致癌融合基因存在于胶质母细胞瘤（GBM）及其他人类癌症的一个亚组中，并已被提议作为新的治疗靶点。我们分析了FGFR-TACC融合基因的频率和分子特征，并探讨了抑制FGFR激酶在GBM以及二级和三级胶质瘤中的治疗效果。
总共对795例胶质瘤（584例GBM、85例野生型二级和三级胶质瘤以及126例异柠檬酸脱氢酶1/2（IDH1/2）突变型二级和三级胶质瘤）进行了FGFR-TACC断点及相关分子特征的筛查。我们还分析了融合基因中FGFR3和TACC3成分的表达。在临床前实验中确定了特异性FGFR抑制剂JNJ-42756493对FGFR3-TACC3阳性胶质瘤的作用。两名晚期FGFR3-TACC3阳性GBM患者接受了JNJ-42756493治疗，并对治疗反应进行了评估。
85例IDH1/2野生型胶质瘤中有3例（3.5%）存在FGFR3-TACC3融合基因，但126例IDH1/2突变型二级和三级胶质瘤中均未发现。584例GBM中有17例（2.9%）存在FGFR-TACC重排。FGFR3-TACC3融合基因与FGFR3免疫染色强且均匀相关。它们与IDH1/2突变和表皮生长因子受体（EGFR）扩增相互排斥，而与细胞周期蛋白依赖性激酶4（CDK4）扩增同时出现。JNJ-42756493在体外和体内均抑制了携带FGFR3-TACC3的胶质瘤细胞的生长。两名接受JNJ-42756493治疗的FGFR3-TACC3重排患者分别表现出病情稳定的临床改善和轻微反应。
逆转录-聚合酶链反应（RT-PCR）测序是鉴定FGFR-TACC阳性患者的一种敏感且特异的方法。FGFR3-TACC3融合基因与肿瘤内融合蛋白的一致表达相关。在接受FGFR抑制剂治疗的FGFR3-TACC3阳性患者中观察到的临床反应支持对FGFR-TACC阳性患者进行FGFR抑制的临床研究。
