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

Abstract

Purpose 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. Experimental Design 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. Results 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. Conclusions 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.

Genetic Landscape of Human Papillomavirus–Associated Head and Neck Cancer and Comparison to Tobacco-Related Tumors

“…Most prominently, in a minority of HPV-positive samples, several authors have reported FGFR3-TACC3 fusions that seem promising as a therapeutic target. [42][43][44] In addition, there was evidence in single samples for structural alterations associated with MET activation. Finally, the most well-described alternative transcript of EGFR, the so-called vIII mutant, was only rarely observed, at a rate of less than 1%.…”

Insights into molecular therapy of glioma: current challenges and next generation blueprint

“…FGFR-TACC fusions involve the tyrosine kinase (TK) domain of FGFR and the coiled-coil domain of TACC proteins. A study involving tumor dependency on FGFR-TACC fusions in preclinical mouse models highlighted the anti-tumor effects of FGFR inhibition (AZD4547 and JNJ-42756493) [32,33] . The targeted inhibition of FGFR-TK in preselected IDH wild-type FGFR-TACC-positive glioma may provide clinical benefits for recurrent glioma patients.…”

Identification of FGFR3-TACC3 gene fusion in metastatic gastric cancer

“…The initial computed tomography (CT) scan at diagnosis demonstrated wall thickening in the lesser curvature of the lower body without any evidence for distant metastasis. He received curative subtotal gastrectomy, Billroth I anastomosis, D2 dissection and the Table 1 that had been reported in the literature [7,[12][13][14][15][16][17][18][19][20][21][22][23][24]. To the best of our knowledge, FG-FR3-TACC3 fusions have not previously been described in GC.…”