Luteolin overcomes acquired resistance to osimertinib in non-small cell lung cancer cells by targeting the HGF-MET-Akt pathway

Guodong Huang; Xinning Liu; Ting Jiang; Yufeng Cao; Mingyu Sang; Xiaomeng Song; Baochen Zhou; Honglin Qu; Houhao Cai; Daijun Xing; Yuecheng Mao; Gaoyang Lin; Xiantao Liu; Xin Zheng

Luteolin overcomes acquired resistance to osimertinib in non-small cell lung cancer cells by targeting the HGF-MET-Akt pathway

Am J Cancer Res. 2023 Sep 15;13(9):4145-4162. eCollection 2023.

Authors

Guodong Huang¹, Xinning Liu², Ting Jiang², Yufeng Cao³, Mingyu Sang⁴, Xiaomeng Song⁵, Baochen Zhou¹, Honglin Qu¹, Houhao Cai¹, Daijun Xing¹, Yuecheng Mao¹, Gaoyang Lin², Xiantao Liu⁶, Xin Zheng³

Affiliations

¹ School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine Jinan 250355, Shandong, PR China.
² Central Laboratory, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital) Qingdao 266033, Shandong, PR China.
³ Cancer Center, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital) Qingdao 266033, Shandong, PR China.
⁴ Preventive Treatment Department, Shouguang Hospital of Traditional Chinese Medicine Weifang 262799, Shandong, PR China.
⁵ Department of Pharmacology, School of Basic Medical Sciences, Shandong University Jinan 250012, Shandong, PR China.
⁶ Department of Respiratory Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine Jinan 250014, Shandong, PR China.

PMID: 37818074
PMCID: PMC10560942

Abstract

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has overcome the acquired resistance of first- and second-generation EGFR-TKIs due to the EGFR T790M mutation in non-small cell lung cancer (NSCLC). However, acquired resistance to osimertinib remains a significant clinical challenge. Luteolin, a natural flavonoid from traditional Chinese medicine, has exerted antitumor effects in various tumors. In this study, we investigated whether the natural flavonoid luteolin can enhance the antitumor effects of osimertinib in NSCLC cells. We established an acquired osimertinib-resistant cell line, H1975/OR, and evaluated the effects of luteolin and osimertinib alone and in combination on proliferation, migration, invasion, and apoptosis of H1975/OR cells. The potential mechanisms by which the combination of luteolin and osimertinib exert their effects were investigated by PCR, western blot, gene silencing, molecular docking, SPR and kinase activity analysis. The combination of luteolin and osimertinib inhibited the proliferation, migration, and invasion of H1975/OR cells and promoted apoptosis. We identified mesenchymal-epithelial transition factor (MET) amplification and overactivation as important resistance mechanisms of H1975/OR cells. The combination downregulated the gene and protein expression of MET and inhibited its protein phosphorylation, thereby blocking the activation of the downstream Akt pathway. Additionally, the mediated effects of MET on the synergistic effect of luteolin and osimertinib were confirmed by silencing of MET. Luteolin strongly bound with nonphosphorylated MET by occupying the active pocket of MET and inhibiting its activation. Notably, the combination also downregulated the expression of autocrine hepatocyte growth factor (HGF), the sole ligand of MET. In conclusion, luteolin can synergize with osimertinib to overcome MET amplification and overactivation-induced acquired resistance to osimertinib by suppressing the HGF-MET-Akt pathway, suggesting the clinical potential of combining luteolin with osimertinib in NSCLC patients with acquired resistance.

Keywords: Non-small cell lung cancer; acquired resistance; luteolin; mesenchymal-epithelial transition factor receptor; osimertinib.