Receptor tyrosine kinase AXL is found upregulated in various types of cancer, including melanoma, and correlates with an aggressive cancer phenotype, inducing cell proliferation and epithelial-to-mesenchymal transition. In addition, AXL has recently been linked to chemotherapy resistance, and inhibition of AXL is found to increase DNA damage and reduce expression of DNA repair proteins. In light of this, we aimed to investigate whether targeting AXL together with DNA damage response proteins would be therapeutically beneficial. Using melanoma cell lines, we observed that combined reduction of AXL and CHK1/CHK2 signaling decreased proliferation, deregulated cell-cycle progression, increased apoptosis, and reduced expression of DNA damage response proteins. Enhanced therapeutic effect of combined treatment, as compared with mono-treatment, was further observed in a patient-derived xenograft model and, of particular interest, when applying a three-dimensional ex vivo spheroid drug sensitivity assay on tumor cells harvested directly from 27 patients with melanoma lymph node metastases. Together, these results indicate that targeting AXL together with the DNA damage response pathway could be a promising treatment strategy in melanoma, and that further investigations in patient groups lacking treatment alternatives should be pursued.

中文翻译：

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靶向 AXL 和 DNA 损伤反应通路作为黑色素瘤的新治疗策略

发现受体酪氨酸激酶 AXL 在各种类型的癌症（包括黑色素瘤）中上调，并且与侵袭性癌症表型相关，诱导细胞增殖和上皮间质转化。此外，最近发现 AXL 与化疗耐药有关，并且发现抑制 AXL 会增加 DNA 损伤并降低 DNA 修复蛋白的表达。鉴于此，我们旨在研究将 AXL 与 DNA 损伤反应蛋白一起靶向是否在治疗上有益。使用黑色素瘤细胞系，我们观察到 AXL 和 CHK1/CHK2 信号的联合减少会降低增殖、解除细胞周期进程的调节、增加细胞凋亡并降低 DNA 损伤反应蛋白的表达。与单一治疗相比，联合治疗的疗效增强，在患者来源的异种移植模型中进一步观察到了，尤其令人感兴趣的是，当对直接从 27 名黑色素瘤淋巴结转移患者中采集的肿瘤细胞应用三维离体球体药物敏感性测定时。总之，这些结果表明，针对 AXL 和 DNA 损伤反应途径可能是黑色素瘤的一种有前景的治疗策略，并且应该对缺乏治疗替代方案的患者群体进行进一步研究。