Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM.
Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM.
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DOI：
10.1158/1078-0432.ccr-17-1577
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发表时间：
2018-01-01
期刊：
影响因子：
--
通讯作者：
Faber AC
中科院分区：
文献类型：
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作者：
Song KA;Niederst MJ;Lochmann TL;Hata AN;Kitai H;Ham J;Floros KV;Hicks MA;Hu H;Mulvey HE;Drier Y;Heisey DAR;Hughes MT;Patel NU;Lockerman EL;Garcia A;Gillepsie S;Archibald HL;Gomez-Caraballo M;Nulton TJ;Windle BE;Piotrowska Z;Sahingur SE;Taylor SM;Dozmorov M;Sequist LV;Bernstein B;Ebi H;Engelman JA;Faber AC
上皮间质转化（EMT）导致对许多靶向治疗和化疗产生耐药性。然而，目前尚不清楚为什么紧急医疗救治会促进耐药性，从而阻碍克服耐药性的进展。我们在 EGFR 突变肺癌中开发了几种 EMT 介导的 EGFR 抑制剂 (EGFRi) 耐药模型，以评估 EMT 介导的耐药的新机制。我们观察到，间充质 EGFR 突变型肺癌通过 BIM 表达不足对 EGFRi 诱导的细胞凋亡具有抵抗力，尽管 EGFRi 治疗后致癌信号传导受到有效抑制，但仍可防止细胞死亡。从机制上讲，我们观察到 EMT 转录因子 ZEB1 通过直接与 BIM 启动子结合并抑制转录来抑制 BIM 表达。通过耗竭ZEB1来解除BIM表达的抑制或用BH3模拟物ABT-263治疗以增强“游离”细胞BIM水平都导致间充质EGFR突变癌症对EGFR抑制剂重新敏感。 EMT 和 BIM 丢失之间的这种关系不仅限于 EGFR 突变型肺癌，在 KRAS 突变型肺癌和包括不同癌症亚型的大型数据集中也观察到了这种关系。总而言之，这些数据揭示了 EMT 与肺癌靶向治疗耐药性之间的新机制联系。
Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it. We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance. We observed that mesenchymal EGFR mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. De-repression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance “free” cellular BIM levels both led to re-sensitization of mesenchymal EGFR mutant cancers to EGFR inhibitors. This relationship between EMT and loss of BIM is not restricted to EGFR mutant lung cancers as it was also observed in KRAS mutant lung cancers and large datasets including different cancer subtypes. Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies.