Mesenchymal stem cells promote erlotinib resistance in non-small cell lung cancer through the HGF-AKT/ERK1/2-OPN pathway.

OBJECTIVES: To investigate the mechanisms by which mesenchymal stem cells (MSCs) contribute to erlotinib resistance in non-small cell lung cancer (NSCLC). METHODS: HCC827 NSCLC cells were treated with MSC-conditioned medium (MSC-CM). Cell viability and apoptosis were evaluated using MTT assays and flow cytometry, respectively. Protein and mRNA expression levels were assessed by western blotting and quantitative real-time PCR. For in vivo validation, a xenograft model was established by co-injecting HCC827 cells and MSCs into NOD/SCID mice. RESULTS: MSC-CM significantly increased cell viability and reduced apoptosis in HCC827 cells following erlotinib treatment, indicating enhanced drug resistance. Mechanistically, MSC-secreted hepatocyte growth factor (HGF) activated AKT and ERK1/2 phosphorylation, thereby bypassing EGFR inhibition by erlotinib. Neutralization of HGF restored erlotinib sensitivity in MSC-CM-treated HCC827 cells. Furthermore, osteopontin (OPN) was transcriptionally upregulated and acted as a resistance enhancer. Inhibition of OPN attenuated MSC-CM-mediated resistance. In vivo, tumors derived from co-injected MSCs and HCC827 cells exhibited significantly greater volume and weight after erlotinib treatment compared to control tumors. CONCLUSIONS: This study identifies a novel MSC-mediated resistance mechanism in which MSC-derived HGF activates compensatory AKT/ERK1/2 signaling, circumventing EGFR blockade by erlotinib. Concurrent upregulation of OPN in NSCLC cells forms a synergistic survival axis under erlotinib pressure. These findings suggest that targeting MSC-derived HGF and tumor-derived OPN may offer promising strategies to overcome erlotinib resistance in NSCLC.