An FGFR3/MYC positive feedback loop provides new opportunities for targeted therapies in bladder cancers.
An FGFR3/MYC positive feedback loop provides new opportunities for targeted therapies in bladder cancers.
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DOI：
10.15252/emmm.201708163
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发表时间：
2018-04
影响因子：
11.1
通讯作者：
Bernard-Pierrot I
中科院分区：
文献类型：
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作者：
Mahe M;Dufour F;Neyret-Kahn H;Moreno-Vega A;Beraud C;Shi M;Hamaidi I;Sanchez-Quiles V;Krucker C;Dorland-Galliot M;Chapeaublanc E;Nicolle R;Lang H;Pouponnot C;Massfelder T;Radvanyi F;Bernard-Pierrot I
FGFR 3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FGFR 3信号传导的异常激活，赋予致癌依赖性，我们在这里研究。我们发现了一个正反馈环，其中来自改变的FGFR 3下游的p38和AKT的激活分别上调MYC mRNA水平和稳定MYC蛋白，导致MYC的积累，其通过与FGFR 3上游的活性增强子结合直接上调FGFR 3表达。通过用FGFR 3、p38、AKT或BET布罗莫结构域抑制剂（JQ 1）处理来破坏膀胱癌细胞系中的该FGFR 3/MYC环，从而防止MYC转录，从而降低体外细胞活力和体内肿瘤生长。携带FGFR 3突变的肿瘤中FGFR 3和MYC水平之间的正相关性以及携带FGFR 3突变的PDX模型中抗FGFR治疗后FGFR 3和MYC水平的降低支持了该环与人膀胱肿瘤的相关性。这些发现为治疗显示异常FGFR 3激活的膀胱肿瘤开辟了新的可能性。
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.