RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics
RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics
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DOI：
10.1172/jci147849
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发表时间：
2021-11-15
影响因子：
15.9
通讯作者：
Mouw, Kent W.
中科院分区：
文献类型：
--
作者：
Bekele, Raie T.;Samant, Amruta S.;Mouw, Kent W.
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子集尿路上皮肿瘤与局灶性扩增的RAF 1（CRAF）激酶基因。RAF 1扩增的肿瘤具有RAF/MEK/ERK信号通路的激活，并表现出管腔基因表达模式。遗传研究表明，RAF 1扩增的肿瘤依赖于RAF 1活性的生存，RAF 1激活的细胞系和患者来源的模型是敏感的可用和新兴的RAF抑制剂，以及结合RAF加MEK抑制。此外，我们发现具有HRAS或NRAS激活突变的膀胱肿瘤依赖于RAF 1介导的信号传导，并且对RAF 1靶向治疗敏感。总之，这些数据将RAF 1激活确定为构成近20%尿路上皮肿瘤的子集的依赖性，并表明靶向RAF 1介导的信号传导代表了合理的治疗策略。
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.