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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 Proceedings of the National Academy of Sciences of the United States of America
Vol 105
Issue 25
Date 2008 Jun 24
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 the 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, Jun 2022).
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 the 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, Jun 2022).
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, Jun 2022).
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 unknown FGFR2 S252W lies within the extracellular domain of the Fgfr2 protein (UniProt.org). The functional effect of S252W is conflicting as it results in loss of ligand specificity, increased Fgfr2 activation, and is transforming in cell culture (PMID: 11121055, PMID: 18552176) but results in a growth advantage relative to wild-type Fgfr2 in a competition assay and transformation activity similar to wild-type Fgfr2 in cultured cells in another study (PMID: 34272467), and therefore, its effect on Fgfr2 protein function is unknown.
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