Bladder cancer is a genetically heterogeneous disease, and novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes. Here, we identified a unique subset of urothelial tumors with focal amplification of the RAF1 (CRAF) kinase gene. RAF1-amplified tumors had activation of the RAF/MEK/ERK signaling pathway and exhibited a luminal gene expression pattern. Genetic studies demonstrated that RAF1-amplified tumors were dependent upon RAF1 activity for survival, and RAF1-activated cell lines and patient-derived models were sensitive to available and emerging RAF inhibitors as well as combined RAF plus MEK inhibition. Furthermore, we found that bladder tumors with HRAS- or NRAS-activating mutations were dependent on RAF1-mediated signaling and were sensitive to RAF1-targeted therapy. Together, these data identified RAF1 activation as a dependency in a subset making up nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rational therapeutic strategy.

中文翻译：

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RAF1 扩增驱动一部分膀胱肿瘤并赋予对 MAPK 导向疗法的敏感性

膀胱癌是一种遗传异质性疾病，需要新的治疗策略来扩大治疗选择并改善临床结果。在这里，我们确定了一个独特的尿路上皮肿瘤子集，具有RAF1 (CRAF) 激酶基因的局灶性扩增。RAF1扩增的肿瘤激活了 RAF/MEK/ERK 信号通路并表现出管腔基因表达模式。遗传学研究表明，RAF1扩增的肿瘤的生存依赖于RAF1活性，并且RAF1激活的细胞系和患者衍生的模型对可用的和新出现的 RAF 抑制剂以及 RAF 加 MEK 抑制的组合敏感。此外，我们发现膀胱肿瘤与HRAS - 或NRAS -激活突变依赖于RAF1介导的信号传导并对 RAF1 靶向治疗敏感。总之，这些数据将RAF1激活确定为占尿路上皮肿瘤近 20% 的子集的依赖性，并表明靶向 RAF1 介导的信号传导代表了一种合理的治疗策略。