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首页> 外文期刊>Biology Open >The effects of crizotinib in a transgenic Drosophila model expressing the human TPM4-ALK fusion gene or TPM4
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The effects of crizotinib in a transgenic Drosophila model expressing the human TPM4-ALK fusion gene or TPM4

机译：克唑替尼在表达人TPM4-ALK融合基因或TPM4的转基因果蝇模型中的作用

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Anaplastic lymphoma kinase (ALK) fusion events lead to constitutive activation of the ALK kinase domain, thereby functioning as oncogenic drivers. These fusion proteins have been identified in numerous cancers. Crizotinib, a small molecule inhibitor of c-Met and ALK, is a Food and Drug Administration-approved drug with reported efficacy in the treatment of cancer. Tropomyosins (TPMs) are a family of actin filament-binding proteins. Altered TPM expression has been found in a variety of human tumors. Inhibitors of cancer-associated TPMs and actin-targeting compounds have been developed, but anti-actin agents have cardiac and respiratory muscle toxicities. In this study, we investigated the sensitivities of human TPM4 (hTPM4), human ALK (hALK), and their fusion gene (hTPM4-hALK) to crizotinib by measuring the lifespan of transgenicDrosophila. Flies overexpressing hTPM4-hALK, hTPM4 and hALK showed decreased lifespans compared with controls. Although crizotinib is an inhibitor of ALK, treatment with crizotinib significantly extended the lifespans ofDrosophilaexpressing hTPM4 and hTPM4-hALK but had no effect on hALK-expressing flies. Autophosphorylation of Tyr1278is necessary for full activation of the ALK domain. We confirmed that hTPM4-hALK was phosphorylated at Tyr1278in a ligand-independent manner, and hTPM4-hALK-expressing flies treated with crizotinib showed a decreased level of Tyr1278phosphorylation compared with untreated hTPM4-hALK-expressing flies, with a greater decrease induced by 1?μM compared with 200?nM crizotinib. Taken together, the results suggest that crizotinib is effective for treating ALK-driven cancer and might be a new therapeutic drug, without cardiac or respiratory muscle toxic effects, for TPM4-expressing cancers.
机译：间变性淋巴瘤激酶（ALK）融合事件导致ALK激酶结构域的组成性激活，从而起到致癌驱动作用。这些融合蛋白已在多种癌症中得到鉴定。克唑替尼是c-Met和ALK的小分子抑制剂，是食品和药物管理局批准的药物，据报道具有治疗癌症的功效。 Tropomyosins（TPM）是肌动蛋白丝结合蛋白家族。已经在多种人类肿瘤中发现了TPM表达的改变。已经开发出与癌症有关的TPM和靶向肌动蛋白的化合物的抑制剂，但抗肌动蛋白剂具有心脏和呼吸肌毒性。在这项研究中，我们通过测量转基因果蝇的寿命，研究了人TPM4（hTPM4），人ALK（hALK）及其融合基因（hTPM4-hALK）对克唑替尼的敏感性。与对照相比，过表达hTPM4-hALK，hTPM4和hALK的果蝇显示寿命缩短。尽管克唑替尼是ALK的抑制剂，但克唑替尼治疗显着延长了果蝇表达hTPM4和hTPM4-hALK的寿命，但对表达hALK的果蝇没有影响。 Tyr1278的自磷酸化对于ALK域的完全激活是必需的。我们证实，hTPM4-hALK在Tyr1278处以配体依赖性方式被磷酸化，与未处理的hTPM4-hALK表达的果蝇相比，用克唑替尼处理的hTPM4-hALK表达的果蝇Tyr1278磷酸化水平降低，由1？ µM与200？nM crizotinib相比。两者合计，结果表明克唑替尼可有效治疗ALK驱动的癌症，并且可能是一种新的治疗药物，对表达TPM4的癌症无心脏或呼吸道肌肉毒性作用。

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