FGFR

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
• Preclinical Evidence

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

Mutations

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