Reference Detail

Ref Type Journal Article
PMID (26048680)
Authors Tanizaki J, Ercan D, Capelletti M, Dodge M, Xu C, Bahcall M, Tricker EM, Butaney M, Calles A, Sholl LM, Hammerman PS, Oxnard GR, Wong KK, Jänne PA
Title Identification of Oncogenic and Drug-Sensitizing Mutations in the Extracellular Domain of FGFR2.
Journal Cancer research
Vol 75
Issue 15
Date 2015 Aug 01
URL
Abstract Text The discovery of oncogenic driver mutations and the subsequent developments in targeted therapies have led to improved outcomes for subsets of lung cancer patients. The identification of additional oncogenic and drug-sensitive alterations may similarly lead to new therapeutic approaches for lung cancer. We identify and characterize novel FGFR2 extracellular domain insertion mutations and demonstrate that they are both oncogenic and sensitive to inhibition by FGFR kinase inhibitors. We demonstrate that the mechanism of FGFR2 activation and subsequent transformation is mediated by ligand-independent dimerization and activation of FGFR2 kinase activity. Both FGFR2-mutant forms are predominantly located in the endoplasmic reticulum and Golgi but nevertheless can activate downstream signaling pathways through their interactions with fibroblast growth factor receptor substrate 2 (FRS2). Our findings provide a rationale for therapeutically targeting this unique subset of FGFR2-mutant cancers as well as insight into their oncogenic mechanisms.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 - TACC3 fusion gain of function FGFR2-TACC3 results from the fusion of FGFR2 and TACC3, resulting in an oncogenic protein as demonstrated by ligand-independent phosphorylation, dimerization, and oncogenic transformation (PMID: 26048680).
S267_D273dup duplication gain of function FGFR2 S267_D273dup (also referred to as A266_S267insSTVVGGD) indicates the insertion of 7 duplicate amino acids, serine (S)-267 through aspartic acid (D)-273, in the Ig-like C2-type domain 3 of the Fgfr2 protein (UniProt.org). S267_D273dup confers a gain of function on Fgfr2 as demonstrated by ligand-independent phosphorylation, dimerization, and oncogenic cell transformation (PMID: 26048680).
T730S missense no effect FGFR2 T730S (corresponds to T729S in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). T730S has activity similar to wild-type Fgfr2 as demonstrated by equivalent substrate phosphorylation and the lack of oncogenic cell transformation (PMID: 26048680).
V755I missense no effect FGFR2 V755I (corresponds to V754I in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). V755I has activity similar to wild-type Fgfr2 as demonstrated by equivalent substrate phosphorylation and the lack of oncogenic cell transformation (PMID: 26048680).
W290_I291delinsC indel gain of function FGFR2 W290_I291delinsC results in a deletion of tryptophan (W) at amino acid 290 and isoleucine (I) at amino acid 291 within the Ig3 region of Fgfr2, combined with the insertion of a cysteine (C) at the same site (UniProt.org). W290_I291delinsC confers a gain of function on Fgfr2 as demonstrated by ligand-independent phosphorylation, dimerization, and oncogenic transformation (PMID: 26048680).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 S267_D273dup Advanced Solid Tumor sensitive BGJ398 Preclinical Actionable In a preclinical study, BGJ398 prevented oncogenic transformation of cells expressing FGFR2 S267_D273dup (PMID: 26048680). 26048680
FGFR2 - TACC3 Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited downstream phosphorylation of Akt and Erk1/2 in cells expressing the fusion, FGFR2 - TACC3 (PMID: 26048680). 26048680
FGFR2 W290_I291delinsC Advanced Solid Tumor sensitive BGJ398 Preclinical Actionable In a preclinical study, BGJ398 prevented oncogenic transformation of cells expressing FGFR2 W290_I291delinsC (PMID: 26048680). 26048680
FGFR2 S267_D273dup Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited downstream phosphorylation of Akt and Erk1/2 in cells expressing Fgfr2 S267_D273dup (PMID: 26048680). 26048680
FGFR2 - TACC3 Advanced Solid Tumor sensitive BGJ398 Preclinical Actionable In a preclinical study, BGJ398 prevented oncogenic transformation of cells expressing FGFR2 - TACC3 (PMID: 26048680). 26048680
FGFR2 W290_I291delinsC Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited downstream phosphorylation of Akt and Erk1/2 in cells expressing Fgfr2 W290_I291delinsC (PMID: 26048680). 26048680