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	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	75	15	2015 Aug 01	3139-46	Cancer Res

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	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
FGFR2	S267_D273dup	duplication	gain of function	FGFR2 S267_D273dup (also referred to as A266_S267insSTVVGGD) indicates the insertion of seven duplicate amino acids, serine (S)-267 through aspartic acid (D)-273, in 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).
FGFR2	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).
FGFR2	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).
FGFR2	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 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
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 S267_D273dup	Advanced Solid Tumor	sensitive	Infigratinib	Preclinical	Actionable	In a preclinical study, Truseltiq (infigratinib) prevented oncogenic transformation of cells expressing FGFR2 S267_D273dup (PMID: 26048680).	26048680
FGFR2 W290_I291delinsC	Advanced Solid Tumor	sensitive	Infigratinib	Preclinical	Actionable	In a preclinical study, Truseltiq (infigratinib) prevented oncogenic transformation of cells expressing FGFR2 W290_I291delinsC (PMID: 26048680).	26048680