Lv Liting, Hua Xin, Liu Jiaxin, Zhan Sutong, Zhang Qianqian, Liang Xiao, Feng Jian, Song Yong
Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu 210002, China.
Department of Oncology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China.
J Biomed Res. 2024 Sep 25:1-15. doi: 10.7555/JBR.38.20240045.
In the present, we aimed to investigate the effect of anlotinib on the potential reversal of osimertinib resistance by inhibiting the formation of epithelial-to-mesenchymal transition (EMT) and angiogenesis. In a clinical case, anlotinib reversed osimertinib resistance in Non-small cell lung cancer (NSCLC). We performed an immunohistochemical experiment on tumor tissues from three non-small cell lung cancer patients exhibiting osimertinib resistance to analyze alterations in the expression levels of EMT markers and vascular endothelial growth factor A (VEGFA) before and after osimertinib resistance. The results revealed the downregulation of E-cadherin, coupled with the upregulation of vimentin and VEGFA in tumor tissues of patients exhibiting osimertinib resistance, compared with the expression in tissues of patients before taking osimertinib. Subsequently, we established osimertinib-resistant cell lines and found that the osimertinib-resistant cells acquired the EMT features. Then, we analyzed the synergistic effects of the combination therapy to verify whether anlotinib could reverse osimertinib resistance by inhibiting EMT. The expression levels of VEGFA and micro-vessels were analyzed in the combination group . Finally, we explored the reversal of osimertinib resistance in combination with anlotinib with 20 nude mice. The combined treatment of osimertinib and anlotinib effectively prevented the metastasis of resistant cells, which also inhibited tumor growth, exerted anti-tumor activity, and ultimately reversed osimertinib resistance in mice. The co-administration of osimertinib and anlotinib demonstrated their synergistic efficacy in inhibiting EMT and angiogenesis in three NSCLC patients, ultimately reversing osimertinib resistance.
目前，我们旨在研究安罗替尼通过抑制上皮-间质转化（EMT）和血管生成的形成对奥希替尼耐药潜在逆转的影响。在一个临床病例中，安罗替尼逆转了非小细胞肺癌（NSCLC）对奥希替尼的耐药性。我们对三名对奥希替尼耐药的非小细胞肺癌患者的肿瘤组织进行了免疫组化实验，以分析奥希替尼耐药前后EMT标志物和血管内皮生长因子A（VEGFA）表达水平的变化。结果显示，与服用奥希替尼前患者组织中的表达相比，对奥希替尼耐药的患者肿瘤组织中E-钙黏蛋白下调，波形蛋白和VEGFA上调。随后，我们建立了奥希替尼耐药细胞系，发现奥希替尼耐药细胞获得了EMT特征。然后，我们分析了联合治疗的协同作用，以验证安罗替尼是否可以通过抑制EMT来逆转奥希替尼耐药性。分析联合组中VEGFA和微血管的表达水平。最后，我们用20只裸鼠探索了安罗替尼联合使用对奥希替尼耐药的逆转作用。奥希替尼和安罗替尼联合治疗有效地阻止了耐药细胞的转移，这也抑制了肿瘤生长，发挥了抗肿瘤活性，并最终逆转了小鼠对奥希替尼的耐药性。奥希替尼和安罗替尼联合给药在三名NSCLC患者中显示出它们在抑制EMT和血管生成方面的协同疗效，最终逆转了奥希替尼耐药性。
