Uterine serous cancer (USC) is aggressive, and the majority of recurrent cases are chemoresistant. Because the receptor tyrosine kinase AXL promotes invasion and metastasis of USC and is implicated in chemoresistance in other cancers, we assessed the role of AXL in paclitaxel resistance in USC, determined the mechanism of action, and sought to restore chemosensitivity by inhibiting AXL in vitro and in vivo. We used short hairpin RNAs and BGB324 to knock down and inhibit AXL. We assessed sensitivity of USC cell lines to paclitaxel and measured paclitaxel intracellular accumulation in vitro in the presence or absence of AXL. We also examined the role of the epithelial–mesenchymal transition (EMT) in AXL-mediated paclitaxel resistance. Finally, we treated USC xenografts with paclitaxel, BGB324, or paclitaxel plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant USC patient tumors and cell lines than in chemosensitive tumors and cell lines. Knockdown or inhibition of AXL increased sensitivity of USC cell lines to paclitaxel in vitro and increased cellular accumulation of paclitaxel. AXL promoted chemoresistance even in cells that underwent the EMT in vitro. Finally, in vivo studies of combination treatment with BGB324 and paclitaxel showed a greater than 51% decrease in tumor volume after 2 weeks of treatment when compared with no treatment or single-agent treatments (P < 0.001). Our results show that AXL expression mediates chemoresistance independent of EMT and prevents accumulation of paclitaxel. This study supports the continued investigation of AXL as a clinical target, particularly in chemoresistant USC. Mol Cancer Ther; 16(12); 2881–91. ©2017 AACR.

中文翻译：

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抑制受体酪氨酸激酶 AXL 可恢复子宫浆液性癌对紫杉醇的化疗敏感性

子宫浆液性癌 (USC) 具有侵袭性，并且大多数复发病例具有化学抗性。由于受体酪氨酸激酶 AXL 促进 USC 的侵袭和转移，并与其他癌症的化学耐药性有关，我们评估了 AXL 在 USC 紫杉醇耐药中的作用，确定了作用机制，并试图通过在体外和体内。我们使用短发夹 RNA 和 BGB324 来敲低和抑制 AXL。我们评估了 USC 细胞系对紫杉醇的敏感性，并在 AXL 存在或不存在的情况下测量了体外紫杉醇细胞内积累。我们还研究了上皮间质转化 (EMT) 在 AXL 介导的紫杉醇耐药中的作用。最后，我们用紫杉醇、BGB324 或紫杉醇加 BGB324 治疗 USC 异种移植物并监测肿瘤负荷。AXL 表达在化学抗性 USC 患者肿瘤和细胞系中高于化学敏感性肿瘤和细胞系。敲除或抑制 AXL 增加了 USC 细胞系对体外紫杉醇的敏感性，并增加了紫杉醇的细胞积累。即使在体外经历 EMT 的细胞中，AXL 也能促进化学抗性。最后，与未治疗或单药治疗相比，BGB324 和紫杉醇联合治疗的体内研究显示，治疗 2 周后肿瘤体积减少了 51% 以上（P < 0.001）。我们的结果表明，AXL 表达介导了独立于 EMT 的化学抗性，并防止了紫杉醇的积累。该研究支持将 AXL 作为临床靶点的持续研究，特别是在化学抗性 USC 中。摩尔癌症治疗; 16(12); 2881-91。©2017 AACR。