Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
Mol Oncol. 2018 Dec;12(12):2191-2208. doi: 10.1002/1878-0261.12395. Epub 2018 Nov 5.
AXL receptor tyrosine kinase is overexpressed in esophageal adenocarcinoma (EAC) and several other types of malignancies; hence, it may be a valuable therapeutic target. Herein, we investigated the role of AXL in regulating c-MYC expression and resistance to the chemotherapeutic agent epirubicin in EAC. Using in vitro EAC cell models, we found that AXL overexpression enhances epirubicin resistance in sensitive cells. Conversely, genetic knockdown or pharmacological inhibition of AXL sensitizes resistant cells to epirubicin. Notably, we showed that inhibition or knockdown of c-MYC markedly sensitizes AXL-dependent resistant cells to epirubicin, and our data demonstrated that AXL promotes epirubicin resistance through transcriptional upregulation of c-MYC. We showed that AXL overexpression significantly increased transcriptional activity, mRNA, and protein levels of c-MYC. Conversely, AXL knockdown reversed these effects. Mechanistic investigations indicated that AXL upregulates c-MYC expression through activation of the AKT/β-catenin signaling pathway. Data from a tumor xenograft mouse model indicated that inhibition of AXL with R428 in combination with epirubicin synergistically suppresses tumor growth and proliferation. Our results demonstrate that AXL promotes epirubicin resistance through transcriptional upregulation of c-MYC in EAC. Our findings support future clinical trials to assess the therapeutic potential of R428 in epirubicin-resistant tumors with overexpression of AXL and activation of c-MYC.
AXL 受体酪氨酸激酶在食管腺癌（EAC）和其他几种恶性肿瘤中过表达；因此，它可能是一个有价值的治疗靶点。在此，我们研究了 AXL 在调节 c-MYC 表达和对化疗药物表柔比星耐药中的作用在 EAC 中。使用体外 EAC 细胞模型，我们发现 AXL 过表达增强了敏感细胞对表柔比星的耐药性。相反，AXL 的基因敲低或药理学抑制使耐药细胞对表柔比星敏感。值得注意的是，我们表明抑制或敲低 c-MYC 可显著增强 AXL 依赖性耐药细胞对表柔比星的敏感性，并且我们的数据表明 AXL 通过转录上调 c-MYC 促进表柔比星耐药性。我们表明 AXL 过表达显著增加了 c-MYC 的转录活性、mRNA 和蛋白水平。相反，AXL 敲低逆转了这些效应。机制研究表明，AXL 通过激活 AKT/β-catenin 信号通路上调 c-MYC 的表达。肿瘤异种移植小鼠模型的数据表明，用 R428 抑制 AXL 与表柔比星联合使用可协同抑制肿瘤生长和增殖。我们的结果表明，AXL 通过在 EAC 中上调 c-MYC 的转录来促进表柔比星耐药性。我们的发现支持未来的临床试验，以评估 R428 在 AXL 过表达和 c-MYC 激活的表柔比星耐药肿瘤中的治疗潜力。
