Anlotinib reverses osimertinib resistance via inhibiting epithelial-to-mesenchymal transition and angiogenesis in non-small cell lung cancer.

Abstract

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 in vitro. Finally, we explored the reversal of osimertinib resistance in combination with anlotinib in vivo 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.