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Background <p>Almonertinib resistance poses a major challenge in treating lung adenocarcinoma (LUAD) with epidermal growth factor receptor (EGFR) mutations. Research indicates that the c-MET/PI3K/AKT signaling pathway and epithelial-mesenchymal transition (EMT) are closely associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Anlotinib, a multi-target TKI, has demonstrated synergistic anti-tumor potential in combination with other TKIs. However, whether its combination with Almonertinib can reverse Almonertinib resistance and the underlying mechanism remain unclear.</p> Methods <p>An Almonertinib-resistant cell line (NCI-H1975-AR) was established in vitro, and a xenograft model was constructed in vivo. The effect of combination therapy on cell viability, apoptosis, invasion, migration capabilities, histopathological changes and proliferation in tumor tissues were assessed. The expression of c-MET/PI3K/AKT pathway, EGFR, FGFR, and EMT markers was examined to explore the molecular mechanism of the combination therapy.</p> Results <p>The combination of Anlotinib and Almonertinib significantly reduced the IC₅₀ of Almonertinib in NCI-H1975-AR cells, promoted apoptosis, and inhibited their invasion and migration capabilities. The combination treatment downregulated the expression of c-MET, p-PI3K, p-AKT, FGFR, EGFR, and Vimentin, while upregulating E-cadherin expression. The sensitizing effect of the combination treatment was partially reversed by the PI3K agonist 740 Y-P. In vivo experiments further confirmed that the combination therapy significantly inhibited tumor growth, reduced tumor volume and weight, downregulated the expression of proliferation markers CD31, PCNA, and Ki67, suppressed the c-MET/PI3K/AKT signaling pathway, downregulated EMT markers, and inhibited the expression of EGFR and FGFR.</p> Conclusion <p>Anlotinib combined with Almonertinib can effectively reverse Almonertinib resistance in lung adenocarcinoma by inhibiting the c-MET/PI3K/AKT signaling pathway, blocking the EMT process, and suppressing the aberrant activation of EGFR/FGFR.</p>

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Anlotinib combined with almonertinib reverses almonertinib resistance in lung adenocarcinoma by inhibiting the c-MET/PI3K/AKT pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Dingdan Lu,
  • Bo Peng,
  • Weiwei Ouyang

摘要

Background

Almonertinib resistance poses a major challenge in treating lung adenocarcinoma (LUAD) with epidermal growth factor receptor (EGFR) mutations. Research indicates that the c-MET/PI3K/AKT signaling pathway and epithelial-mesenchymal transition (EMT) are closely associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Anlotinib, a multi-target TKI, has demonstrated synergistic anti-tumor potential in combination with other TKIs. However, whether its combination with Almonertinib can reverse Almonertinib resistance and the underlying mechanism remain unclear.

Methods

An Almonertinib-resistant cell line (NCI-H1975-AR) was established in vitro, and a xenograft model was constructed in vivo. The effect of combination therapy on cell viability, apoptosis, invasion, migration capabilities, histopathological changes and proliferation in tumor tissues were assessed. The expression of c-MET/PI3K/AKT pathway, EGFR, FGFR, and EMT markers was examined to explore the molecular mechanism of the combination therapy.

Results

The combination of Anlotinib and Almonertinib significantly reduced the IC₅₀ of Almonertinib in NCI-H1975-AR cells, promoted apoptosis, and inhibited their invasion and migration capabilities. The combination treatment downregulated the expression of c-MET, p-PI3K, p-AKT, FGFR, EGFR, and Vimentin, while upregulating E-cadherin expression. The sensitizing effect of the combination treatment was partially reversed by the PI3K agonist 740 Y-P. In vivo experiments further confirmed that the combination therapy significantly inhibited tumor growth, reduced tumor volume and weight, downregulated the expression of proliferation markers CD31, PCNA, and Ki67, suppressed the c-MET/PI3K/AKT signaling pathway, downregulated EMT markers, and inhibited the expression of EGFR and FGFR.

Conclusion

Anlotinib combined with Almonertinib can effectively reverse Almonertinib resistance in lung adenocarcinoma by inhibiting the c-MET/PI3K/AKT signaling pathway, blocking the EMT process, and suppressing the aberrant activation of EGFR/FGFR.