Epithelial-to-Mesenchymal Transition Is a Mechanism of ALK Inhibitor Resistance in Lung Cancer Independent of ALK Mutation Status
Epithelial-to-Mesenchymal Transition Is a Mechanism of ALK Inhibitor Resistance in Lung Cancer Independent of ALK Mutation Status
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DOI：
10.1158/0008-5472.can-18-2052
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发表时间：
2019-04-01
期刊：
影响因子：
11.2
通讯作者：
Yano, Seiji
中科院分区：
文献类型：
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作者：
Fukuda, Koji;Takeuchi, Shinji;Yano, Seiji
在约40%对ALK抑制剂耐药的ALK重排肺癌中可检测到ALK基因突变。虽然上皮-间质转化（EMT）是对各种靶向药物耐药的一种机制，但其与ALK抑制剂耐药的关系在很大程度上尚不清楚。在这项研究中，我们报告了ALK突变体L1196 M和EMT在ALK重排肺癌患者的单个克唑替尼耐药病灶中同时检测到。数字PCR分析结合EMT标记物IHC染色后的显微切割显示，ALK L1196 M主要在上皮型肿瘤细胞中检测到，表明间充质表型和ALK突变可以共存为ALK耐药癌症的独立机制。克唑替尼耐药肺癌细胞的临床前实验表明，EMT与miR-200 c表达降低和ZEB 1表达增加相关，导致对新一代ALK抑制剂alectinib、ceritinib和lorlatinib的交叉耐药。用组蛋白去乙酰化酶（HDAC）抑制剂quisinostat预处理通过在体外和体内逆转EMT克服了这种抗性。这些研究结果表明，HDAC抑制剂预处理后，一种新的ALK抑制剂可能是有用的，以规避耐药构成的共存的耐药突变和EMT在异质tumor.Significance：这些研究结果表明，HDAC和ALK受体酪氨酸激酶活性的双重抑制提供了一种手段，以规避克唑替尼耐药的肺癌。
Mutations in the ALK gene are detectable in approximately 40% of ALK-rearranged lung cancers resistant to ALK inhibitors. Although epithelial-to-mesenchymal transition (EMT) is a mechanism of resistance to various targeted drugs, its involvement in ALK inhibitor resistance is largely unknown. In this study, we report that both ALK-mutant L1196M and EMT were concomitantly detected in a single crizotinib-resistant lesion in a patient with ALK-rearranged lung cancer. Digital PCR analyses combined with microdissection after IHC staining for EMT markers revealed that ALK L1196M was predominantly detected in epithelial-type tumor cells, indicating that mesenchymal phenotype and ALK mutation can coexist as independent mechanisms underlying ALK inhibitor-resistant cancers. Preclinical experiments with crizotinib-resistant lung cancer cells showed that EMT associated with decreased expression of miR-200c and increased expression of ZEB1 caused cross-resistance to new-generation ALK inhibitors alectinib, ceritinib, and lorlatinib. Pretreatment with the histone deacetylase (HDAC) inhibitor quisinostat overcame this resistance by reverting EMT in vitro and in vivo. These findings indicate that HDAC inhibitor pretreatment followed by a new ALK inhibitor may be useful to circumvent resistance constituted by coexistence of resistance mutations and EMT in the heterogeneous tumor.Significance: These findings show that dual inhibition of HDAC and ALK receptor tyrosine kinase activities provides a means to circumvent crizotinib resistance in lung cancer.