The FGFR signalling pathway
Adapted from Corn PG et al. 2013 and Yang et al. 2019.[1][2]
FGFR3 is a member of a highly conserved and widely distributed tyrosine kinase receptor family that activates numerous physiological processes and can also be associated with tumour growth.[3][4]
In the FGF/FGFR signalling pathway, FGF ligand binding triggers autophosphorylation of FGFR.[1] Docking proteins such as FRS2a and PLCγ then activate downstream pathways, including RAS/RAF/MEK, PI3K/AKT/mTOR and STAT.[1]
The role of FGFR alterations in tumourigenesis
The majority of FGFR genetic alterations lead to gain-of-function.[3][4] Aberrant FGFR signalling can drive tumourigenesis and is implicated in:[4][5]
- Cancer cell survival
- Neoangiogenesis
- Metastatic dissemination
- Cancer cell proliferation
- Invasion
- Response to anticancer therapies
In addition, some of the mechanisms underlying the role of aberrant FGFR signalling in tumourigenesis include:[6]
- Protein overexpression
- Activating mutations
- Oncogenic fusions
- Autocrine or paracrine signalling
- Angiogenesis
- EMT
- Deregulation of binding partners
Adapted from Babina IS and Turner NC 2017.[6]
Prevalence of FGFR3 alterations in different cancer types
In certain types of cancer, an improved understanding of molecular pathology has enabled the arrival of precision medicine, which can help improve treatment outcomes for patient subpopulations with the appropriate biomarkers.[7][8]
In particular, FGFR3 alterations are a potential tumour driver identified in multiple tumour types.[3][4][5][9]
In an analysis of 4,853 cancers, those that commonly harboured FGFR3 alterations included:*,[10]
- 22.2% of urothelial
- 4.2% of glioma
- 2.5% of endometrial
- 2.3% of pancreatic exocrine
- 2.3% of renal cell
- 1.7% of ovarian/fallopian
- 1.2% of gastric/GE junction
- 1.2% of non-small cell lung cancer
- 0.9% of head and neck, squamous cell
- 0.8% of breast
- 0.6% of sarcoma
- 0.3% of colorectal
As can be seen, FGFR3 alterations are most commonly found in UC and have been identified across all grades and/or stages of bladder cancer.[3][9]
Understanding the molecular subtypes of bladder cancer can help reveal potential biomarkers, identify distinct patient subpopulations and inform treatment decision-making[11][12]
Explore more
What could the identification of molecular subtypes and distinct genetic disease drivers mean for the management of advanced LA/mUC?
How might optimised molecular testing protocols enable the timely identification of relevant genetic alterations that could be driving your patients’ tumour growth?[7][13][14][15]
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*Samples from 4,853 cancers of various types were analysed for FGFR alterations at the request of a physician. UCs include cancers of the renal pelvis (21 cases), ureter (6), bladder (90) and not otherwise specified (9). Gliomas include glioblastoma (84 cases), astrocytoma (21), ependymoma (7), oligodendroglioma (17) and glioma not otherwise specified (15).[3][10]
AKT: protein kinase B; EMT: epithelial–mesenchymal transition; ERK: extracellular signal-regulated kinase; FGF: fibroblast growth factor; FGFR: fibroblast growth factor receptor; FRS2a: FGF receptor substrate 2a; GE: gastroesophageal; GRb2: growth factor receptor bound protein 2; HSP: heparan sulfate proteoglycans; LA: locally advanced; MAPK: mitogen-activated protein kinase; MEK: MAPK/ERK kinase; MKP3: mitogen-activated protein kinase phosphatase 3; mTOR: mammalian target of rapamycin; mUC: metastatic UC; P: phosphate; PI3K: phosphoinositide 3-kinase; PLCγ: phospholipase C gamma; PTEN: phosphatase and TENsin homolog deleted on chromosome 10; RAF: rapidly accelerated fibrosarcoma kinase; RAS: retrovirus-associated deoxyribonucleic acid; SEF: spatial-temporal regulator of MAPK signalling; SOS: Son of Sevenless; STAT: signal transducer and activator of transcription; TK: tyrosine kinase; UC: urothelial carcinoma.
