Reference Detail

Ref Type

Journal Article

PMID

(18552176)

Authors

Dutt A, Salvesen HB, Chen TH, Ramos AH, Onofrio RC, Hatton C, Nicoletti R, Winckler W, Grewal R, Hanna M, Wyhs N, Ziaugra L, Richter DJ, Trovik J, Engelsen IB, Stefansson IM, Fennell T, Cibulskis K, Zody MC, Akslen LA, Gabriel S, Wong KK, Sellers WR, Meyerson M, Greulich H

Title

Drug-sensitive FGFR2 mutations in endometrial carcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America	105	25	2008 Jun 24	8713-7	Proc Natl Acad Sci U S A

URL

Abstract Text

Oncogenic activation of tyrosine kinases is a common mechanism of carcinogenesis and, given the druggable nature of these enzymes, an attractive target for anticancer therapy. Here, we show that somatic mutations of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene, FGFR2, are present in 12% of endometrial carcinomas, with additional instances found in lung squamous cell carcinoma and cervical carcinoma. These FGFR2 mutations, many of which are identical to mutations associated with congenital craniofacial developmental disorders, are constitutively activated and oncogenic when ectopically expressed in NIH 3T3 cells. Inhibition of FGFR2 kinase activity in endometrial carcinoma cell lines bearing such FGFR2 mutations inhibits transformation and survival, implicating FGFR2 as a novel therapeutic target in endometrial carcinoma.

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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
FGFR2	A314D	missense	unknown	FGFR2 A314D lies within Ig-like C2-type domain 3 of the Fgfr2 protein (UniProt.org). A314D has been identified in sequencing studies (PMID: 18552176), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2024).
FGFR2	A389T	missense	unknown	FGFR2 A389T lies within the transmembrane domain of the Fgfr2 protein (UniProt.org). A389T results in proliferation similar to wild-type Fgfr2 in a competition assay (PMID: 34272467) and is not transforming in culture in one study (PMID: 18552176), but increased transformation activity in cultured cells in another study (PMID: 34272467), and therefore, its effect on Fgfr2 protein function is unknown.
FGFR2	A97T	missense	unknown	FGFR2 A97T lies within Ig-like C2-type domain 1 of the Fgfr2 protein (UniProt.org). A97T has been identified in sequencing studies (PMID: 28581676, PMID: 18552176), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2024).
FGFR2	D101Y	missense	gain of function	FGFR2 D101Y lies within the extracellular Ig-like C2-type domain 1 of the Fgfr2 protein (UniProt.org). D101Y results in a growth advantage relative to wild-type Fgfr2 in a competition assay (PMID: 34272467) and increased transformation activity in cultured cells (PMID: 34272467, PMID: 18552176).
FGFR2	N211I	missense	unknown	FGFR2 N211I lies within Ig-like C2-type domain 2 of the Fgfr2 protein (UniProt.org). N211I has been identified in sequencing studies (PMID: 18552176), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2024).
FGFR2	N549K	missense	gain of function	FGFR2 N549K lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N549K confers a gain of function to the Fgfr2 protein resulting in a growth advantage relative to wild-type Fgfr2 in a competition assay, increased transformation activity in cultured cells (PMID: 34272467), oncogenic transformation in culture (PMID: 18552176, PMID: 17803937, PMID: 29533785) and increased MAPK pathway signaling in cultured cells (PMID: 19147536).	Y
FGFR2	S252W	missense	gain of function - predicted	FGFR2 S252W lies within the extracellular domain of the Fgfr2 protein (UniProt.org). S252W results in a growth advantage relative to wild-type Fgfr2 in a competition assay and transformation activity similar to overexpressed Fgfr2 in cultured cells (PMID: 34272467), and results in loss of ligand specificity, increased Fgfr2 phosphorylation, increased FGF7-stimulated shedding of HB-EGF, and is transforming in cell culture (PMID: 11121055, PMID: 18552176, PMID: 37759450), and therefore, is predicted to lead to a gain of Fgfr2 protein function.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR2 S252W	endometrial cancer	sensitive	E7090	Preclinical - Cell culture	Actionable	In a preclinical study, an endometrial cancer cell line harboring FGFR2 S252W (PMID: 18552176) demonstrated sensitivity to E7090 in culture, resulting in decreased cell viability (PMID: 27535969).	18552176 27535969