Anlotinib combined with almonertinib reverses almonertinib resistance in lung adenocarcinoma by inhibiting the c-MET/PI3K/AKT pathway.
- 1Department of Thoracic Oncology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550008, China.
- 2Department of Oncology, Xingyi People's Hospital Affiliated to Guizhou Medical University, Xingyi, 562400, China.
- 3Department of Thoracic Oncology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550008, China. [email protected].
Abstract
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.
Related
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BibTeX
@article{lu2026anlotinib,
title = {{Anlotinib combined with almonertinib reverses almonertinib resistance in lung adenocarcinoma by inhibiting the c-MET/PI3K/AKT pathway.}},
author = {Dingdan Lu and Bo Peng and Weiwei Ouyang},
journal = {World journal of surgical oncology},
year = {2026},
month = aug,
doi = {10.1186/s12957-026-04521-1},
url = {https://europepmc.org/article/MED/42972594},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Anlotinib combined with almonertinib reverses almonertinib resistance in lung adenocarcinoma by inhibiting the c-MET/PI3K/AKT pathway.
AU - Dingdan Lu
AU - Bo Peng
AU - Weiwei Ouyang
PY - 2026
DA - 2026/08/05
JO - World journal of surgical oncology
DO - 10.1186/s12957-026-04521-1
UR - https://europepmc.org/article/MED/42972594
AB - 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.
SN - 1477-7819
ER -