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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, May 2020).
FGFR2 A389T missense no effect - predicted FGFR2 A389T lies within the transmembrane domain of the Fgfr2 protein (UniProt.org). A389T is not transforming in cell culture (PMID: 18552176), and therefore, it is predicted to have no effect on Fgfr2 protein function.
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, May 2020).
FGFR2 D101Y missense gain of function - predicted FGFR2 D101Y lies within the extracellular Ig-like C2-type domain 1 of the Fgfr2 protein (UniProt.org). D101Y results in the transformation of cells in culture (PMID: 18552176) and therefore, is predicted to result in a gain of FGFR2 protein function.
FGFR2 K310R missense no effect - predicted FGFR2 K310R lies within the Ig-like C2-type domain 3 of the Fgfr2 protein (UniProt.org). K310R has not been biochemically characterized, however, is not transforming in cell culture (PMID: 18552176) and therefore, is predicted to have no effect on Fgfr2 protein function.
FGFR2 N211I missense unknown FGFR2 N211I lies within the 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, May 2020).
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 oncogenic transformation in cell-based studies (PMID: 18552176, PMID: 17803937, PMID: 29533785) and increased MAPK pathway signaling in cultured cells (PMID: 19147536). Y
FGFR2 S252W missense gain of function FGFR2 S252W lies within the extracellular domain of the Fgfr2 protein (UniProt.org). S252W results in loss of ligand specificity, increased Fgfr2 activation, and is transforming in cell culture (PMID: 11121055, PMID: 18552176).
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