Chordoma Foundation


The Fibroblast Growth Factor Receptor family includes 4 receptor tyrosine kinases (RTKs). RTKs code for proteins on the surface of the cell that become activated when bound by their ligands. When FGFs bind to FGFRs, the FGFR pathway becomes activated and signals for the phosphorylation of downstream proteins including FRS2α.

Relevant Locations:
FGFR1, Chromosome 8p12
FGFR2, Chromosome 10q26
FGFR3, Chromosome 4p16
FGFR4, Chromosome 5q35

Signal transduction through FGF/FGFR ultimately influences signaling through numerous pathways implicated in tumorigenesis, including RAS-RAF-MEK-MAPK, PI3k-Akt-mTOR, and Stat3. FGFR signaling is associated with increased cellular proliferation and resistance to apoptosis, enhanced motility and invasiveness, and increased resistance to cytotoxic therapies in multiple tumor types1

FGFR in Chordoma

It has been established that brachyury, of known importance in the biology of chordoma, is regulated by FGFR signaling in lower vertebrates.2 3 4 5 Studies have shown that FGFRs are expressed in chordoma and that the FGF/FGFR signaling pathway is activated. Knowledge of FGFRs role in other cancers and its activation in chordoma has led researchers to explore whether modulating the pathway with targeted therapies could have antitumor effects, and a group recently showed that an FGFR inhibitor could inhibit chordoma cell line growth.6 This page contains a summary of published research exploring the role of FGFR signaling and evaluating its inhibition as a treatment for chordoma.

Molecular Evidence

Copy Number Variation

Chromosomal Aberrations: Chromosome 5 gain at the locus where FGFR4 resides has been observed in 7/21 chordomas.7 No amplification has been observed among 50 samples.8


Despite the fact that FGFR mutations are well documented and lead to various developmental syndromes, no activating germline or somatic mutations were found in FGFR1, 2, 3, or 4 in any of the 23 chordoma samples tested.8

Gene Expression

Overexpression of FGFR1 has been observed in patient tumors using RNASeq.9

Protein Expression

Nearly all chordomas tested express at least one of the FGFRs, and a third express all four.8 Chordoma cell lines U-CH1, U-CH2, and JHC7 express FGFR2 and FGFR3, but not FGFR1 or FGFR4.6

Protein Activation

Phosphorylation of FGFR substrates FRSα, MEK, and ERK is further evidence that the FGFR pathway is active in chordomas.  Which FGFRs are responsible for the activation has not been elucidated.8 10   Activated FGFR3, though present in some samples studied by RTK activation array, was not statistically significant.11 Hypermethylation of the KL tumor suppressor gene (which normally modulates FGF signaling by binding to FGGFR) has been observed in 10/10 chordomas tested.12

Pathway Interactions

Treating cell lines with an antibody that neutralized FGF2  inhibited MEK/ERK phosphorylation, decreased brachyury expression, suppressed cell growth, and increased both caspase 3 activity and DNA fragmentation. These consequences suggest that endocrine FGF2 signaling plays a role in chordoma progression. When FGF2 was active, it led to phosphorylation of FRSα, which in turn induced phosphorylation of MEK and ERK, ultimately upregulating brachyury expression.6

Preclinical Evidence

In-vitro Efficacy

  • PD173074: Treatment of chordoma cell lines JHC7, U-CH1, and U-CH2 with this FGFR inhibitor blocked the effects of FGF2, leading to an increase in caspase 3 activity and DNA fragmentation while inhibiting cell growth. It blocked FGF2-induced phosphorylation of FRSa, reduced phosphorylation of MEK1/2 and ERK1/2, and decreased levels of brachyury.6

Hoffmann A, Czichos S, Kaps C, et al. The T-box transcription factor Brachyury mediates cartilage development in mesenchymal stem cell line C3H10T1/2. J Cell Sci. 2002;115(Pt 4):769-781. [PubMed]
Matsumoto J, Kumano G, Nishida H. Direct activation by Ets and Zic is required for initial expression of the Brachyury gene in the ascidian notochord. Dev Biol. 2007;306(2):870-882. [PubMed]
Griffin K, Kimelman D. Interplay between FGF, one-eyed pinhead, and T-box transcription factors during zebrafish posterior development. Dev Biol. 2003;264(2):456-466. [PubMed]
Isaacs H, Pownall M, Slack J. eFGF regulates Xbra expression during Xenopus gastrulation. EMBO J. 1994;13(19):4469-4481. [PubMed]
Yasuo H, Hudson C. FGF8/17/18 functions together with FGF9/16/20 during formation of the notochord in Ciona embryos. Dev Biol. 2007;302(1):92-103. [PubMed]
Hu Y, Mintz A, Shah S, Quinones-Hinojosa A, Hsu W. The FGFR/MEK/ERK/brachyury pathway is critical for chordoma cell growth and survival. Carcinogenesis. 2014;35(7):1491-1499. [PubMed]
Hallor K, Staaf J, Jönsson G, et al. Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation. Br J Cancer. 2008;98(2):434-442. [PubMed]
Shalaby A, Presneau N, Idowu B, et al. Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas. Mod Pathol. 2009;22(8):996-1005. [PubMed]
Liang W, Dardis C, Helland A, et al. Identification of therapeutic targets in chordoma through comprehensive genomic and transcriptomic analyses. Cold Spring Harb Mol Case Stud. October 2018. [PubMed]
Fasig J, Dupont W, LaFleur B, Olson S, Cates J. Immunohistochemical analysis of receptor tyrosine kinase signal transduction activity in chordoma. Neuropathol Appl Neurobiol. 2008;34(1):95-104. [PubMed]
Dewaele B, Maggiani F, Floris G, et al. Frequent activation of EGFR in advanced chordomas. Clin Sarcoma Res. 2011;1(1):4. [PubMed]
Rinner B, Weinhaeusel A, Lohberger B, et al. Chordoma characterization of significant changes of the DNA methylation pattern. PLoS One. 2013;8(3):e56609. [PubMed]

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