KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub.
KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub.
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DOI：
10.1016/j.celrep.2017.08.037
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发表时间：
2017-09-05
期刊：
影响因子：
8.8
通讯作者：
Cagan RL
中科院分区：
文献类型：
--
作者：
Das TK;Cagan RL
基因融合越来越被认为是重要的癌症驱动因素。最近发现KIF5B-RET基因是肺腺癌的主要致癌基因。以人KIF5B-RET为靶点，在果蝇体内引导多方面的转化，包括过度增殖、上皮向间充质的转变、侵袭和显著的内向足突的延伸。KIF5B-RET转化的人支气管细胞株表现出相似的转化过程，包括内陷足样过程。通过遗传学和生物化学相结合的研究，我们证明了KIF5B-RET的激动素和激酶域共同作用，建立了一个新出现的微管和RAB囊泡依赖的RET-SRC-EGFR-FGFR‘信号中枢’。我们证明，仅设计用于抑制RET的药物在KIF5B-RET转化的细胞中效果不佳。然而，将RET抑制剂索拉非尼与靶向EGFR或微管或FGFR的药物结合在一起，在果蝇和人类细胞系KIF5B-RET模型中都能产生强大的疗效。这项工作证明了在探索融合的全部生物学以确定合理的治疗策略方面的效用。Das和Cagan发现，KIF5B-RET融合癌蛋白的每个部分都招募了不同的成分，以组装一个促进内含菌形成的多激酶致癌信号枢纽。这表明KIF5B-RET中枢的多个激酶成分需要同时作为治疗的靶点。
Gene fusions are increasingly recognized as important cancer drivers. KIF5B-RET gene was recently identified as a primary driver in a subset of lung adenocarcinomas. Targeting human KIF5B-RET to epithelia in Drosophila directed multiple aspects of transformation including hyperproliferation, epithelial-to-mesenchymal transition, invasion, and extension of striking invadopodia-like processes. KIF5B-RET-transformed human bronchial cell line showed similar aspects of transformation including invadopodia-like processes. Through a combination of genetic and biochemical studies we demonstrate that the kinesin and kinase domains of KIF5B-RET act together to establish an emergent microtubule and RAB vesicle-dependent RET-SRC-EGFR-FGFR ‘signaling hub’. We demonstrate that drugs designed to inhibit RET alone work poorly in KIF5B-RET-transformed cells. However, combining the RET inhibitor sorafenib with drugs that target EGFR or microtubules or FGFR led to strong efficacy in both Drosophila and human cell line KIF5B-RET models. This work demonstrates the utility in exploring the full biology of fusions to identify rational therapeutic strategies. Das and Cagan find that each portion of the KIF5B-RET fusion oncoprotein recruits different components to assemble a multi-kinase oncogenic signaling hub that promotes invadopodia formation. This suggests that multiple kinase components of this KIF5B-RET hub need to be simultaneously targeted therapeutically.
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82.9
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通讯作者：
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作者：
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