An FGFR 3/ MYC positive feedback loop provides new opportunities for targeted therapies in bladder cancers

Abstract

FGFR3 alterations (mutations or translocation) are among the most frequent genetic events in bladder carcinoma. They lead to an aberrant activation of FGFR3 signaling, conferring an oncogenic dependence, which we studied here. We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates MYC mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates FGFR3 expression by binding to active enhancers upstream from FGFR3. Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing MYC transcription decreased cell viability in vitro and tumor growth in vivo. A relevance of this loop to human bladder tumors was supported by the positive correlation between FGFR3 and MYC levels in tumors bearing FGFR3 mutations, and the decrease in FGFR3 and MYC levels following anti‐FGFR treatment in a PDX model bearing an FGFR3 mutation. These findings open up new possibilities for the treatment of bladder tumors displaying aberrant FGFR3 activation.

LncRNA GClnc1 promotes proliferation and invasion of bladder cancer through activation of MYC

“…Results indicated that the mRNA expression levels of MYC, HMGA1, IGF1R, and INSR were significantly decreased after inhibition of GClnc1 in bladder cancer cells. MYC was the lowest down-regulated oncogene after inhibition of GClnc1 in bladder cancer cells and has been proven to be a vital regulator of bladder cancer progression (27)(28)(29). Thus, in this study, the LIN28B/let-7a/MYC pathway was investigated.…”

“…7C, D). MYC has been well characterized as a critical regulator of cancer progression and invasion in bladder cancer (27)(28)(29). Thus, MYC was chosen for the further study.…”

Predictive biomarkers for drug response in bladder cancer

“…50,51 Activation of this signaling was actually found to be enriched in a subset of bladder cancer, 17,36,52 and rather considered targetable and druggable. 53,54 Further studies are required to validate alterations in these genes as chemosensitivity biomarkers and explore possible mechanisms of sensitivity caused by the activation of these signaling pathways. Predictive biomarkers reported so far for CDDP sensitivity in bladder cancer have not been consistent among studies, potentially because of the reliance on small cohorts, retrospective or post-hoc analyses, the difference in chemotherapy regimens, outcome measurements and sequencing techniques, consequently producing conflicting results.…”

APOBEC-mediated Mutagenesis as a Likely Cause of FGFR3 S249C Mutation Over-representation in Bladder Cancer

“…To identify genes regulated by FGFR3 with different mutations, MGH-U3 and UMUC-14 bladder cancer cells endogenously expressing FGFR3-Y375C and FGFR3-S249C, respectively, were transfected for 72 hrs with three FGFR3 siRNAs (described in Mahe et al [15]). mRNA was extracted and purified with the RNeasy Mini kit (Qiagen).…”

“…mRNA was extracted and purified with the RNeasy Mini kit (Qiagen). Total RNA (200 ng) from control and siRNA-treated MGH-U3 and UMUC-14 cells was analyzed with the Affymetrix human exon 1.0 ST array and the Affymetrix U133 plus 2 array, respectively, as previously described [15]. Experiments using MGH-U3 cells have been described by Mahe et al [15] and the microarray data were available from GEO (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE84733.…”