Reference Detail

Ref Type

Journal Article

PMID

(31316618)

Authors

Xie X, Lin J, Zhong Y, Fu M, Tang A

Title

FGFR3S249C mutation promotes chemoresistance by activating Akt signaling in bladder cancer cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Experimental and therapeutic medicine	18	2	2019 Aug	1226-1234	Exp Ther Med

URL

Abstract Text

Fibroblast growth factor receptor 3 (FGFR3) is a high frequency mutant gene in bladder cancer (BCa) and has become a promising therapeutic target due to its involvement in cell proliferation and migration. However, whether and how FGFR3 mutations affects BCa cell chemosensitivity is unknown. The current study aimed to elucidate the role of the FGFR3S249C mutation in the development of chemoresistance in BCa cells. The results revealed that 97-7 (FGFR3S249C) cells had decreased sensitivity to cisplatin compared with 5637 (FGFR3WT) and T24 (FGFR3WT) cells. The ratio of phosphorylated-Akt/total-Akt was higher in 97-7 (FGFR3S249C) cells, which was reversed by knockdown of FGFR3. Furthermore, inhibition of Akt signaling by GDC0068 or LY294002 increased the cisplatin sensitivity of 97-7 (FGFR3S249C) cells. GDC0068 or LY294002 was also revealed to augment the effects of cisplatin on 97-7 (FGFR3S249C) cell proliferation and apoptosis. The results of the present study demonstrated that the FGFR3S249C mutation promotes chemoresistance in BCa cells by activating the Akt signaling pathway. The FGFR3S249C mutation may therefore be used as a predictor of chemosensitivity in patients with BCa.

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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
FGFR3	S249C	missense	gain of function	FGFR3 S249C lies within the linker region between IgD2 and IgD3 of the Fgfr3 protein (PMID: 19381019). S249C results in stabilized homodimer formation and constitutive Fgfr3 phosphorylation in vitro (PMID: 17384684), ligand-independent cell proliferation in culture (PMID: 19381019, PMID: 29533785), increased Akt signaling (PMID: 31316618), a growth advantage relative to wild-type Fgfr3 in a competition assay, and increased transformation activity in cultured cells (PMID: 34272467).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR3 S249C	urinary bladder cancer	predicted - sensitive	Cisplatin + LY294002	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of LY294002 treatment resulted in enhanced sensitivity of bladder cancer cells expressing FGFR3 S249C to treatment with Platinol (cisplatin) in culture, demonstrating a greater reduction in cell proliferation and increased apoptotic activity when compared to Platinol (cisplatin) alone (PMID: 31316618).	31316618
FGFR3 S249C	urinary bladder cancer	predicted - sensitive	Cisplatin + Ipatasertib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of Ipatasertib (GDC0068) treatment resulted in enhanced sensitivity of bladder cancer cells expressing FGFR3 S249C to treatment with Platinol (cisplatin) in culture, demonstrating a greater reduction in cell proliferation and increased apoptotic activity when compared to Platinol (cisplatin) alone (PMID: 31316618).	31316618