2. Academic Validation
  3. C-terminal Truncation and Fusion Partner Determine Oncogenicity of FGFR3

C-terminal Truncation and Fusion Partner Determine Oncogenicity of FGFR3

  • Cancer Res. 2025 Dec 29. doi: 10.1158/0008-5472.CAN-24-2648.
Julia Yemelyanenko 1,  Jinhyuk Bhin 2,  Eline van der Burg 1,  Anne Paulien Drenth 1,  Jessica K Lee 3,  Catrin Lutz 1,  Lea Dörner 1,  Ellen Wientjens 1,  Sjoerd Klarenbeek 4,  Ji-Ying Song 1,  Hyeonjin Moon 5,  Stefano Annunziato 1,  Natalie Proost 1,  Bjørn Siteur 6,  Jeffrey S Ross 7,  Marieke van de Ven 1,  Olaf van Tellingen 8,  Shridar Ganesan 9,  Lodewyk F A Wessels 10,  Daniel Zingg 11,  Jos Jonkers 1
Affiliations

Affiliations

  • 1 The Netherlands Cancer Institute Amsterdam Netherlands.
  • 2 Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital Seoul Korea (South), Republic of.
  • 3 Foundation Medicine Boston, MA United States.
  • 4 Royal GD (Netherlands) Deventer Netherlands.
  • 5 Gangnam Severance Hospital, Yonsei University College of Medicine Seoul Korea (South), Republic of.
  • 6 Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital Amsterdam Netherlands.
  • 7 SUNY Upstate Medical University Syracuse, NY United States.
  • 8 Netherlands Cancer Institute Amsterdam Netherlands.
  • 9 Rutgers Cancer Institute of New Jersey New Brunswick, New Jersey United States.
  • 10 The Netherlands Cancer Institute Amsterdam, NH Netherlands.
  • 11 Genentech United States.
PMID: 41460723 DOI: 10.1158/0008-5472.CAN-24-2648
Abstract

Genomic alterations affecting components of the Fibroblast Growth Factor (FGF) signaling axis can trigger aberrant pathway activation and tumor development. Genomic truncation of the FGF receptor 2 (FGFR2) exon 18 (E18) disrupts the FGFR2 carboxy-terminal tail (C-tail), acting as a potent driver alteration across multiple tumor types. Here, we analyzed human oncogenomic datasets to reveal that E18 truncations are similarly prevalent in FGFR3, an FGFR2 paralog. FGFR3 E18 truncations primarily occurred due to rearrangements (REs) that involve transforming acidic coiled-coil containing protein 3 (TACC3), resulting in FGFR3ΔE18-TACC3 gene fusions. In contrast to E18-truncated FGFR2, functional in vitro and in vivo examination of Fgfr3 variants demonstrated that the truncation of Fgfr3 E18 is insufficient to promote oncogenic activity in cell lines or in the lungs and mammary glands of mice. Only the combination of an Fgfr3 E18 truncation with a RE partner gene that encodes a receptor-dimerizing domain resulted in the development of tumors, which were sensitive to FGFR inhibition. Overall, these findings suggest that patients with cancers that are positive for rearranged FGFR3 resulting in E18 truncation and a fusion to dimerizing partners should be considered for FGFR-targeted therapies.

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