Drosophila Cancer Models Identify Functional Differences between Ret Fusions.
Drosophila Cancer Models Identify Functional Differences between Ret Fusions.
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DOI：
10.1016/j.celrep.2016.08.019
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发表时间：
2016-09-13
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：
Levinson S;Cagan RL
我们生成并比较了RET融合CCDC 6-RET和NCOA 4-RET的果蝇模型。两种RET融合体都指导细胞迁移、分层和经历EMT，并且当广泛表达时都导致致死性。在检查的所有表型中，NCOA 4-RET比CCDC 6-RET更严重，反映了它们对患者的影响。针对果蝇激酶组和癌症药物库的功能筛选发现，CCDC 6-RET和NCOA 4-RET通过不同的信号网络起作用，并显示出不同的药物敏感性。结合来自激酶组和药物筛选的数据，将WEE 1抑制剂AZD 1775加上多激酶抑制剂索拉非尼确定为特异性针对NCOA 4-RET的协同药物组合。我们的工作强调了识别和定制患者治疗的重要性，以其特定的RET融合亚型，并确定了一种多靶向治疗，可以证明对含有NCOA 4-RET融合的肿瘤有效。Levinson和Cagan研究了两种果蝇RET融合模型。他们发现N-末端有助于融合蛋白的整体功能，包括它们对治疗药物的反应。遗传和化学遗传筛选鉴定索拉非尼加AZD 1775的药物组合对NCOA 4-RET融合有效。
We generated and compared Drosophila models of RET fusions CCDC6-RET and NCOA4-RET. Both RET fusions directed cells to migrate, delaminate, and undergo EMT, and both resulted in lethality when broadly expressed. In all phenotypes examined NCOA4-RET was more severe than CCDC6-RET, mirroring their effects on patients. A functional screen against the Drosophila kinome and against a library of cancer drugs found that CCDC6-RET and NCOA4-RET acted through different signaling networks and displayed distinct drug sensitivities. Combining data from the kinome and drug screens identified the WEE1 inhibitor AZD1775 plus the multi-kinase inhibitor sorafenib as a synergistic drug combination that is specific for NCOA4-RET. Our work emphasizes the importance of identifying and tailoring a patient’s treatment to their specific RET fusion isoform and identifies a multi-targeted therapy that may prove effective against tumors containing the NCOA4-RET fusion. Levinson and Cagan examine two Drosophila RET-fusion models. They find that the N-terminus contributes to the overall function of fusion proteins, including their response to therapeutics. Genetic and chemical genetic screens identify a drug combination of sorafenib plus AZD1775 as effective against the NCOA4-RET fusion.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
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DOI：
10.1016/j.ecl.2008.02.006
发表时间：
2008-06-01
影响因子：
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作者：
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影响因子：
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作者：
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