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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 Experimental and therapeutic medicine
Vol 18
Issue 2
Date 2019 Aug
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 confers a gain of function to the Fgfr3 protein as demonstrated by stabilized homodimer formation and constitutive phosphorylation in vitro (PMID: 17384684), constitutive 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), and therefore, is predicted to lead to a gain of Fgfr3 protein function. 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 + 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
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