Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma PMID: 25609060

ADC Targets in Oncology

2026-04-10

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

Clin Cancer Res. 2015 Jul 15;21(14):3307-17. doi: 10.1158/1078-0432.CCR-14-2199.

Anna Luisa Di Stefano ¹ , Alessandra Fucci ² , Veronique Frattini ² , Marianne Labussiere ³ , Karima Mokhtari ⁴ , Pietro Zoppoli ² , Yannick Marie ⁵ , Aurelie Bruno ³ , Blandine Boisselier ³ , Marine Giry ³ , Julien Savatovsky ⁶ , Mehdi Touat ⁷ , Hayat Belaid ⁸ , Aurelie Kamoun ⁹ , Ahmed Idbaih ¹⁰ , Caroline Houillier ¹¹ , Feng R Luo ¹² , Jean-Charles Soria ⁷ , Josep Tabernero ¹³ , Marica Eoli ¹⁴ , Rosina Paterra ¹⁴ , Stephen Yip ¹⁵ , Kevin Petrecca ¹⁶ , Jennifer A Chan ¹⁷ , Gaetano Finocchiaro ¹⁴ , Anna Lasorella ¹⁸ , Marc Sanson ¹⁹ , Antonio Iavarone ²⁰

Affiliations

1. 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.
2. Institute for Cancer Genetics, Columbia University Medical Center, New York, New York.
3. Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, Paris, France.
4. 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.
5. 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.
6. Fondation Ophtalmologique A. de Rothschild, Paris, France.
7. Drug Development Department, Gustave Roussy Cancer Center, Paris, France.
8. AP-HP, Groupe Hospitalier Pitié Salpêtrière, Department of Neurosurgery, Paris, France.
9. Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France.
10. 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.
11. AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris, France.
12. Janssen Pharmaceutical Companies of Johnson and Johnson, Titusville, New Jersey.
13. Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
14. Fondazione I.R.C.C.S Istituto Neurologico C. Besta, Milan, Italy.
15. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
16. Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.
17. University of Calgary, Calgary, Canada.
18. 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.
19. 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. [email protected] [email protected].
20. 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. [email protected] [email protected].

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.