Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Sci Transl Med. 2019 Mar 13;11(483). doi: 10.1126/scitranslmed.aaq1238.
Mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors have failed to show clinical benefit in Kirsten rat sarcoma () mutant lung cancer due to various resistance mechanisms. To identify differential therapeutic sensitivities between epithelial and mesenchymal lung tumors, we performed in vivo small hairpin RNA screens, proteomic profiling, and analysis of patient tumor datasets, which revealed an inverse correlation between mitogen-activated protein kinase (MAPK) signaling dependency and a zinc finger E-box binding homeobox 1 (ZEB1)-regulated epithelial-to-mesenchymal transition. Mechanistic studies determined that MAPK signaling dependency in epithelial lung cancer cells is due to the scaffold protein interleukin-17 receptor D (IL17RD), which is directly repressed by ZEB1. Lung tumors in multiple mutant murine models with increased ZEB1 displayed low IL17RD expression, accompanied by MAPK-independent tumor growth and therapeutic resistance to MEK inhibition. Suppression of ZEB1 function with miR-200 expression or the histone deacetylase inhibitor mocetinostat sensitized resistant cancer cells to MEK inhibition and markedly reduced in vivo tumor growth, showing a promising combinatorial treatment strategy for mutant cancers. In human lung tumor samples, high ZEB1 and low IL17RD expression correlated with low MAPK signaling, presenting potential markers that predict patient response to MEK inhibitors.
丝裂原活化蛋白激酶（MAPK）激酶（MEK）抑制剂由于各种耐药机制，未能在 Kirsten 大鼠肉瘤（）突变型肺癌中显示出临床获益。为了鉴定上皮性和间质性肺肿瘤之间的差异治疗敏感性，我们进行了体内短发夹 RNA 筛选、蛋白质组学分析和患者肿瘤数据集分析，结果显示 MAPK 信号依赖性与锌指 E 盒结合同源盒 1（ZEB1）调控的上皮-间充质转化之间存在负相关。机制研究确定上皮性肺癌细胞中 MAPK 信号依赖性是由于支架蛋白白细胞介素 17 受体 D（IL17RD），其直接受 ZEB1 抑制。在 ZEB1 表达增加的多个 突变型鼠模型中的肺肿瘤显示低 IL17RD 表达，同时伴有 MAPK 非依赖性肿瘤生长和对 MEK 抑制的耐药性。用 miR-200 表达或组蛋白去乙酰化酶抑制剂 mocetinostat 抑制 ZEB1 功能可使耐药癌细胞对 MEK 抑制敏感，并显著减少体内肿瘤生长，为 突变型癌症提供了一种有前途的联合治疗策略。在人肺肿瘤样本中，高 ZEB1 和低 IL17RD 表达与低 MAPK 信号相关，提示可能的标志物可预测患者对 MEK 抑制剂的反应。
