PATIENT SUMMARY: We propose that APOBEC-mediated mutagenesis can generate clinically relevant driver mutations even within suboptimal motifs, such as in the case of FGFR3S249C, one of the most common mutations in bladder cancer.
Silencing or inhibition of mutant FGFR3 in bladder cancer cell lines is associated with decreased malignant potential, confirming its important driver role in UC.
Recent precision medicine has shown that mutations in BC are frequently observed in FGFR3, RAS and PIK3CA genes, all of which correlate with RAS signaling networks.
The aim of this paper was to report the most pivotal trials that evaluated different families of targeted therapy in the treatment of BC, according to their biomarkers (FGFR3, EGFR, HER2, VEGF and PI3K/AKT/mTOR).
We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates <i>MYC</i> mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates <i>FGFR3</i> expression by binding to active enhancers upstream from <i>FGFR3</i> Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing <i>MYC</i> transcription decreased cell viability <i>in vitro</i> and tumor growth <i>in vivo</i> A relevance of this loop to human bladder tumors was supported by the positive correlation between <i>FGFR3</i> and <i>MYC</i> levels in tumors bearing <i>FGFR3</i> mutations, and the decrease in FGFR3 and MYC levels following anti-FGFR treatment in a PDX model bearing an <i>FGFR3</i> mutation.
Here we show that HDAC6 loss or inhibition reduces FGFR3 accumulation in cells made tumorigenic by ectopic expression of a mutant activated version of FGFR3 together with the MYC oncoprotein and in a bladder cancer cell line whose tumorigenicity is dependent on expression of a translocated version of FGFR3.
The GSE41035 dataset downloaded from Gene Expression Omnibus was used to identify the differentially expressed genes (DEGs) between bladder cancer cell line RT112 with or without depletion of FGFR3, and gene ontology enrichment analysis was performed.
Further investigation showed that FGFR3 knockdown resulted in downregulation of DAPK1 in bladder cancer cell line, suggesting that FGFR3 may be an upstream factor of DAPK1.
The present study examined the utility of fibroblast growth factor receptor 3 (<i>FGFR3</i>) mutation status and gene expression as a prognostic marker in primary pT1 bladder cancer (BC).
Knockdown of endogenous FGFR3 impaired the activity of daidzein against bladder cancer, which suggested that the effect of daidzein was mainly mediated by FGFR3 pathway.
In non-invasive BC, these mutations were related to high risk and grade (p<0.0001) as well as progression to muscle-invasive disease (p=0.01), whereas FGFR3 mutations were observed in low-grade BC (p=0.02) and patients with recurrences (p=0.05).
Our findings are consistent with the results of the TCGA data set for the "squamous-like" subtype of bladder cancer (n = 85), which revealed reduced overall expression of FGFR1 and FGFR2 in tumors compared to normal tissue, while expression of FGFR3 remained high.