Inhibition of Bruton's tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemness.
Inhibition of Bruton's tyrosine kinase as a therapeutic strategy for chemoresistant oral squamous cell carcinoma and potential suppression of cancer stemness.
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DOI：
10.1038/s41389-021-00308-z
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发表时间：
2021-02-27
期刊：
影响因子：
6.2
通讯作者：
Lin CS
中科院分区：
文献类型：
--
作者：
Liu SC;Wu YC;Huang CM;Hsieh MS;Huang TY;Huang CS;Hsu TN;Huang MS;Lee WH;Yeh CT;Lin CS
局部晚期口腔鳞状细胞癌（OSCC）需要多模式治疗，包括手术和同步放化疗（CCRT）。ccrt耐药和复发的癌症预后较差。我们研究了布鲁顿酪氨酸激酶（BTK）对耐ccrt的OSCC组织的影响。ibrutinib（一种一流的BTK抑制剂）对干细胞样OSCC肿瘤球的作用进行了测试。使用70例OSCC患者的组织样本构建组织阵列。检测人OSCC细胞株SAS、TW2.6和HSC-3。采用伤口愈合、Matrigel侵袭、肿瘤球形成试验、免疫荧光分析和流式细胞术研究BTK敲低（shBTK）、依鲁替尼、顺铂、依鲁替尼/顺铂联合使用对OSCC细胞的影响。我们证明了BTK在临床抗ccrt的OSCC组织阵列中异常高表达，这导致我们当地三服务综合医院和自由访问的TCGA OSCC队列的总生存率较低。shBTK显著下调SAS肿瘤球中干细胞标记物Nanog、CD133、T细胞免疫球蛋白-3 （TIM-3）和kr<s:1> ppel样因子4 (KLF4)，减弱OSCC细胞迁移和集落形成。依鲁替尼减少了醛脱氢酶（ALDH）丰富的OSCC细胞的数量，并以剂量依赖性的方式减少了肿瘤球的形成、迁移和侵袭。与依鲁替尼或顺铂单药治疗相比，依鲁替尼/顺铂联合治疗可显著减少ALDH + OSCC肿瘤球的形成，增强细胞凋亡。这些结果表明，ibrutinib通过失调BTK/CD133信号传导有效抑制OSCC细胞的cscs样表型。依鲁替尼/顺铂联合用药可考虑将来的临床应用。
Locally advanced oral squamous cell carcinoma (OSCC) requires multimodal therapy, including surgery and concurrent chemoradiotherapy (CCRT). CCRT-resistant and recurrent cancer has a poor prognosis. We investigated the effects of Bruton’s tyrosine kinase (BTK) on CCRT-resistant OSCC tissues. The effect of ibrutinib, a first-in-class BTK inhibitor, was tested on stem cell-like OSCC tumorspheres. A tissue array was constructed using tissue samples from 70 patients with OSCC. Human OSCC cell lines, SAS, TW2.6 and HSC-3, were examined. Wound healing, Matrigel invasion, and tumorsphere formation assays, as well as immunofluorescence analysis and flow cytometry, were used to investigate the effects of BTK knockdown (shBTK), ibrutinib, cisplatin, and ibrutinib/cisplatin combination on OSCC cells. We demonstrated that BTK was aberrantly highly expressed in the clinical CCRT-resistant OSCC tissue array, which resulted in poor overall survival in our local Tri-Service General Hospital and freely accessible TCGA OSCC cohorts. shBTK significantly downregulated the stemness markers Nanog, CD133, T cell immunoglobulin-3 (TIM-3), and Krüppel-like factor 4 (KLF4) in SAS tumorspheres and attenuated OSCC cell migration and colony formation. Ibrutinib reduced the number of aldehyde dehydrogenase (ALDH)-rich OSCC cells and reduced tumorsphere formation, migration, and invasion in a dose-dependent manner. Compared with ibrutinib or cisplatin monotherapy, the ibrutinib/cisplatin combination significantly reduced the formation of ALDH + OSCC tumorspheres and enhanced apoptosis. These results demonstrate that ibrutinib effectively inhibits the CSCs-like phenotype of OSCC cells through dysregulation of BTK/CD133 signaling. The ibrutinib/cisplatin combination may be considered for future clinical use.
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