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

Abstract

In the present study, we aimed to investigate whether anlotinib reverses osimertinib resistance by inhibiting the formation of epithelial-mesenchymal transition (EMT) and angiogenesis. In a clinical case, anlotinib reversed osimertinib resistance in non-small cell lung cancer (NSCLC). Therefore, we performed immunohistochemical analyses on tumor tissues from three NSCLC patients with osimertinib resistance to analyze alterations in the expression levels of EMT markers and vascular endothelial growth factor A (VEGFA) before and after the development of 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 those in tissues from patients before receiving osimertinib. Subsequently, we established osimertinib-resistant (Osi-R) cell lines and found that the Osi-R cells acquired EMT features. Next, 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 tube formation were analyzed in the combination group in vitro. Finally, we determined the reversal of osimertinib resistance by the combination of osimertinib and anlotinib in vivo using 20 nude mice. The combined treatment of osimertinib and anlotinib effectively prevented the metastasis of Osi-R cells, inhibited tumor growth, exerted antitumor activity, and ultimately reversed osimertinib resistance in mice. The co-administration of osimertinib and anlotinib demonstrated synergistic efficacy in inhibiting EMT and angiogenesis in three NSCLC patients, ultimately reversing osimertinib resistance.

Keywords

non-small cell lung cancer / osimertinib / anlotinib / resistance / epithelial-to-mesenchymal transition

Fundings

This work was supported by the National Natural Science Foundation of China (Grant Nos. 82172728 and 82370096).

Acknowledgments

The authors would like to thank all the reviewers who participated in the review and MJEditor (www.mjeditor.com) for their linguistic assistance during the preparation of this manuscript.

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