Reference Detail

Ref Type

Journal Article

PMID

(27053219)

Authors

von Mässenhausen A, Deng M, Billig H, Queisser A, Vogel W, Kristiansen G, Schröck A, Bootz F, Göke F, Franzen A, Heasley L, Kirfel J, Brägelmann J, Perner S

Title

Evaluation of FGFR3 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Targeted oncology	11	5	2016 Oct	631-642	Target Oncol

URL

Abstract Text

Although head and neck squamous cell carcinoma (HNSCC) is the sixth most common tumour entity worldwide, it remains a clinical challenge. Large-scale explorative genomic projects have identified several genes as potential targets for therapy, including fibroblast growth factor receptor 3 (FGFR3).The aim of this study was to investigate the biological significance of wild-type and mutated FGFR3 to evaluate its potential as a novel therapeutic target in HNSCC.FGFR3 protein expression was analysed in a large HNSCC tissue cohort (n = 536) and FGFR3 mRNA expression from The Cancer Genome Atlas (TCGA; n = 520). Moreover, FGFR3 wild-type and mutant versions were overexpressed in vitro, and both proliferation and migration was assessed with and without BGJ398 (a specific FGFR1-3 inhibitor) treatment.Although FGFR3 expression for both cohorts decreased during tumour progression, high FGFR3 expression levels were observed in a small subset of patients. In vitro, FGFR3 overexpression led to increased proliferation, whereas migration was not altered. Moreover, FGFR3-overexpressing cells were more sensitive to BGJ398. Cells overexpressing FGFR3 mutant versions showed increased proliferation compared to wild-type FGFR3 under serum-reduced conditions and were largely as sensitive as the wild-type protein to BGJ398.Taken together, the results of this study demonstrate that although FGFR3 expression decreases during HNSSC progression, it plays an important role in tumour cell proliferation and thus may be a potential target for therapy in selected patients suffering from this dismal tumour entity.

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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
FGFR3	D764H	missense	unknown	FGFR3 D764H (corresponds to D762H in the canonical isoform) lies within the cytoplasmic domain of the Fgfr3 protein (UniProt.org). D764H results in increased proliferation in some cell culture conditions, but not others (PMID: 27053219) and therefore, its effect on Fgfr3 protein function is unknown.
FGFR3	D788N	missense	unknown	FGFR3 D788N (corresponds to D785N in the canonical isoform) lies within the cytoplasmic domain of the Fgfr3 protein (UniProt.org). D788N results in increased proliferation in some cell culture conditions, but not others (PMID: 27053219) and therefore, its effect on Fgfr3 protein function is unknown.
FGFR3	S131L	missense	unknown	FGFR3 S131L lies within the extracellular domain of the Fgfr3 protein (UniProt.org). The functional effect of S131L is conflicting, as it results in decreased proliferation and cell viability compared to wild-type Fgfr3 in one study (PMID: 29533785), however, in another study, demonstrates increased cell proliferation under some cell culture conditions (PMID: 27053219), and therefore, its effect on Fgfr3 protein function is unknown.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR3 D788N	head and neck squamous cell carcinoma	no benefit	Infigratinib	Preclinical - Cell culture	Actionable	In a preclinical study, Truseltiq (infigratinib) inhibited proliferation of a head and neck squamous cell carcinoma cell line expressing FGFR3 D788N in culture, however, cells expressing FGFR3 D788N did not demonstrate increased sensitivity to Truseltiq (infigratinib) compared to cells expressing wild-type FGFR3 (PMID: 27053219).	27053219
FGFR3 D764H	head and neck squamous cell carcinoma	no benefit	Infigratinib	Preclinical - Cell culture	Actionable	In a preclinical study, Truseltiq (infigratinib) inhibited proliferation of a head and neck squamous cell carcinoma cell line expressing FGFR3 D764H in culture, however, cells expressing FGFR3 D764H did not demonstrate increased sensitivity to Truseltiq (infigratinib) compared to cells expressing wild-type FGFR3 (PMID: 27053219).	27053219
FGFR3 S131L	head and neck squamous cell carcinoma	decreased response	Infigratinib	Preclinical - Cell culture	Actionable	In a preclinical study, a head and neck squamous cell carcinoma cell line expressing FGFR3 S131L demonstrated decreased sensitivity to Truseltiq (infigratinib) compared to cells expressing wild-type FGFR3 in culture (PMID: 27053219).	27053219