Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is a major advance in treating NSCLC with EGFR-activating mutations. However, acquired resistance, due partially to secondary mutations limits their use. Here we report that NSCLC cells with acquired resistance to gefitinib or osimertinib (AZD9291) exhibit EMT features, with a decrease in E-cadherin, and increases in vimentin and stemness, without possessing any EGFR secondary mutations. Knockdown of E-cadherin in parental cells increased gefitinib resistance and stemness, while knockdown of vimentin in resistant cells resulted in opposite effects. Src activation and Hakai upregulation were found in gefitinib-resistant cells. Knockdown of Hakai elevated E-cadherin expression, attenuated stemness, and resensitized the cells to gefitinib. Clinical cancer specimens with acquired gefitinib resistance also showed a decrease in E-cadherin and an increase in Hakai expression. The dual HDAC and HMGR inhibitor JMF3086 inhibited the Src/Hakai and Hakai/E-cadherin interaction to reverse E-cadherin expression, and attenuated vimentin and stemness to restore gefitinib sensitivity. The EMT features of AZD9291-resistant H1975 cells were related to the upregulation of Zeb1. Both gefitinib and AZD9291 sensitivity was restored by JMF3086 through reversing EMT. Our study not only revealed a common mechanism of EMT in both gefitinib and AZD9291 resistance beyond EGFR mutations per se, but also provides a new strategy to overcome it.

中文翻译：

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超出EGFR突变本身的上皮-间充质转变（EMT）是获得性耐药EGFR TKI的常见机制。

表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）是治疗具有EGFR激活突变的NSCLC的重要进展。然而，部分由于次级突变而获得的抗性限制了它们的使用。在这里，我们报道对吉非替尼或奥西替尼（AZD9291）具有耐药性的NSCLC细胞表现出EMT功能，其中E-钙黏着蛋白减少，波形蛋白和茎干增加，而没有任何EGFR二次突变。E-钙粘蛋白在亲代细胞中的敲除增加了吉非替尼的耐药性和干性，而在抵抗细胞中波形蛋白的敲除则产生了相反的作用。在耐吉非替尼的细胞中发现了Src激活和Hakai上调。敲除Hakai可以提高E-cadherin的表达，减轻干性，并使细胞对吉非替尼重新敏感。具有获得性吉非替尼耐药性的临床癌症标本也显示E-钙黏着蛋白减少和Hakai表达增加。HDAC和HMGR双重抑制剂JMF3086抑制Src / Hakai和Hakai / E-钙粘蛋白相互作用以逆转E-钙粘蛋白表达，并减弱波形蛋白和茎干以恢复吉非替尼敏感性。耐AZD9291的H1975细胞的EMT特征与Zeb1的上调有关。JMF3086通过反转EMT恢复了吉非替尼和AZD9291的敏感性。我们的研究不仅揭示了吉非替尼和AZD9291耐药性中除EGFR突变本身以外的EMT的常见机制，而且还提供了克服它的新策略。HDAC和HMGR双重抑制剂JMF3086抑制Src / Hakai和Hakai / E-钙粘蛋白相互作用以逆转E-钙粘蛋白表达，并减弱波形蛋白和茎干以恢复吉非替尼敏感性。耐AZD9291的H1975细胞的EMT特征与Zeb1的上调有关。JMF3086通过反转EMT恢复了吉非替尼和AZD9291的敏感性。我们的研究不仅揭示了吉非替尼和AZD9291耐药性中除EGFR突变本身以外的EMT的常见机制，而且还提供了克服它的新策略。HDAC和HMGR双重抑制剂JMF3086抑制Src / Hakai和Hakai / E-钙粘蛋白相互作用以逆转E-钙粘蛋白表达，并减弱波形蛋白和茎干以恢复吉非替尼敏感性。耐AZD9291的H1975细胞的EMT特征与Zeb1的上调有关。JMF3086通过反转EMT恢复了吉非替尼和AZD9291的敏感性。我们的研究不仅揭示了吉非替尼和AZD9291耐药性中除EGFR突变本身以外的EMT的常见机制，而且还提供了克服它的新策略。