Reference Detail

Ref Type

Journal Article

PMID

(27271022)

Authors

Sethakorn N, O'Donnell PH

Title

Spectrum of genomic alterations in FGFR3: current appraisal of the potential role of FGFR3 in advanced urothelial carcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
BJU international	118	5	2016 Nov	681-691	BJU Int

URL

Abstract Text

Molecular analysis has identified subsets of urothelial carcinoma (UC) expressing distinct genetic signatures. Genomic alterations in the oncogenic fibroblast growth factor receptor 3 (FGFR3) pathway are among the most well described in UC and have led to extensive and ongoing investigation of FGFR3-targeted therapies in this disease, although no new drugs have yet been approved. Given the unmet need for effective treatments in advanced and metastatic UC, a better understanding of the known molecular alterations of FGFR3 and of the previous and ongoing clinical investigations of this promising target in UC deserves attention. The objective of the present review is to describe the landscape of alterations and biology of FGFR3 in UC, comprehensively summarize the current state of UC clinical trials of FGFR3 inhibitors, and discuss future therapeutic applications. Using the Pubmed and Clinicaltrials.gov databases, articles describing the spectrum and biological activity of FGFR3 genomic alterations and trials of FGFR3 inhibitors in UC were identified. Search terms included 'FGFR3 genomic alterations' and 'urothelial cancer' or 'bladder cancer'. Genomic alterations, including translocations and activating mutations, are increasingly described in advanced and metastatic UC. The majority of clinical trials have been performed in unselected populations; however, recent studies have reported encouraging preliminary data. We argue that routine use of molecular genomic tumour analysis in UC may inform selection of patients for appropriate trials and we further investigate the potential of FGFR3 as a meaningful clinical target for this difficult disease.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
FGFR3	D222N	missense	unknown	FGFR3 D222N lies within Ig-like C2-type domain 2 of the Fgfr3 protein (UniProt.org). D222N has been identified in the scientific literature (PMID: 27271022), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Mar 2024).
FGFR3	G235D	missense	unknown	FGFR3 G235D lies within Ig-like C2-type domain 2 of the Fgfr3 protein (UniProt.org). G235D has been identified in the scientific literature (PMID: 27271022), but has not been biochemically characterized and therefore, its effect on Fgfr3 protein function is unknown (PubMed, Mar 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR3 S249C	renal pelvis transitional cell carcinoma	predicted - sensitive	Pazopanib	Clinical Study	Actionable	In a case study, a patient with urothelial carcinoma of the renal pelvis harboring FGFR3 S249C demonstrated a partial response lasting 9 months following treatment with Votrient (pazopanib) (PMID: 27271022).	27271022