Osimertinib and dihydroartemisinin: a novel drug combination targeting head and neck squamous cell carcinoma
Osimertinib and dihydroartemisinin: a novel drug combination targeting head and neck squamous cell carcinoma
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DOI：
10.21037/atm.2019.10.80
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发表时间：
2019-11-01
影响因子：
--
通讯作者：
Cao, Peng
中科院分区：
文献类型：
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作者：
Chaib, Imane;Cai, Xueting;Cao, Peng
背景：复发性和转移性头颈鳞状细胞癌（HNSCC）的预后很差，即使采用化疗、靶向治疗和免疫治疗的不同组合进行治疗，无进展生存期和总生存期也有限。我们在体外和体内探索了表皮生长因子受体 (EGFR) 抑制剂奥希替尼单独使用以及与二氢青蒿素 (DHA) 联合使用对 HNSCC 的作用。方法：在 FaDu 和 CAL27 HNSCC 细胞系中测试了奥希替尼与 DHA 的组合。在培养细胞和小鼠异种移植物中进行肿瘤细胞增殖测定。对相关信号通路进行Western blotting分析，探讨DHA及其组合抑制作用的分子机制。其他抑制信号转导和转录激活因子 3 (STAT3)、Src 家族激酶 (SFK)、鞘氨醇激酶 1 (SPHK1) 或受体酪氨酸激酶 (RTK) AXL 的化合物也在体外与奥希替尼联合使用。 结果：奥希替尼与 DHA 联合时对 FaDu 和 CAL27 HNSCC 细胞发挥协同细胞毒性。 DHA 逆转了奥希替尼诱导的 STAT3 和 Src 磷酸化。双重组合抑制AXL表达。奥希替尼联合 DHA 组合的抗癌潜力在小鼠 FaDu 和 CAL27 异种移植物上得到了体内验证，没有明显的副作用。结论：结果表明，奥希替尼和 DHA 联合治疗作为一种再利用的抗癌药物，可能成为复发性和/或转移性 HNSCC 患者的一种新的治疗策略。研究结果强烈表明，有必要进行临床试验来确认该组合的益处。
Background: Recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) has a dismal prognosis with limited progression-free survival and overall survival, even when treated with different combinations of chemotherapy, targeted therapies and immunotherapy. We explored in vitro and in vivo the effect of the epidermal growth factor receptor (EGFR) inhibitor, osimertinib, alone and in combination with dihydroartemisinin (DHA) in HNSCC.Methods: The combination of osimertinib with DHA was tested in the FaDu and CAL27 HNSCC cell lines. Tumor cell proliferation assays were conducted in cultured cells and mouse xenografts. Western blotting analysis of related signal pathways was performed to investigate the molecular mechanisms of the inhibitory effect of DHA and the combination. Other compounds, which inhibit signal transducer and activator of transcription 3 (STAT3), Src-family kinases (SFKs), sphingosine kinase 1 (SPHK1), or the receptor tyrosine kinase (RTK) AXL were also combined with osimertinib in vitro.Results: Osimertinib exerted synergistic cytotoxicity toward FaDu and CAL27 HNSCC cells when combined with DHA. DHA reversed the osimertinib-induced STAT3 and Src phosphorylation. The double combination inhibited AXL expression. The anticancer potential of osimertinib plus DHA combination was validated in vivo on FaDu and CAL27 xenografts in mice without notable side effects.Conclusions: The results illustrate that the combinatory therapy of osimertinib and DHA, as a repurposing anticancer drug, could be a novel therapeutic strategy for recurrent and/or metastatic HNSCC patients. The findings strongly indicate that a clinical trial is warranted to confirm the benefit of the combination.