Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University, Paris, France.
CNRS, UMR144, Sorbonne Universités UPMC Université Paris 06, Paris, France.
EMBO Mol Med. 2018 Apr;10(4). doi: 10.15252/emmm.201708163.
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 mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates expression by binding to active enhancers upstream from Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing transcription decreased cell viability and tumor growth A relevance of this loop to human bladder tumors was supported by the positive correlation between and levels in tumors bearing mutations, and the decrease in FGFR3 and MYC levels following anti-FGFR treatment in a PDX model bearing an mutation. These findings open up new possibilities for the treatment of bladder tumors displaying aberrant FGFR3 activation.
FGFR3 改变（突变或易位）是膀胱癌中最常见的遗传事件之一。它们导致 FGFR3 信号的异常激活，赋予致癌依赖性，我们在这里对此进行了研究。我们发现了一个正反馈回路，其中改变的 FGFR3 下游的 p38 和 AKT 的激活分别上调 mRNA 水平并稳定 MYC 蛋白，导致 MYC 的积累，其通过与 的上游活性增强子结合直接上调 的表达。通过用 FGFR3、p38、AKT 或 BET 溴结构域抑制剂（JQ1）处理破坏膀胱癌细胞系中的这种 FGFR3/MYC 环，可防止 转录，从而降低细胞活力和肿瘤生长。在携带 突变的肿瘤中， 和 水平之间存在正相关，以及在携带 突变的 PDX 模型中，抗 FGFR 治疗后 FGFR3 和 MYC 水平降低，这支持了这种循环与人类膀胱癌之间的相关性。这些发现为显示异常 FGFR3 激活的膀胱癌的治疗开辟了新的可能性。
