HIF‐1 Inhibitor YC‐1 Reverses the Acquired Resistance of EGFR‐Mutant HCC827 Cell Line with MET Amplification to Gefitinib

Abstract

Background. Acquired resistance occurred in the majority of nonsmall cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) therapy, and this may be related to the activation of the HIF-1 pathway. Therefore, we examined the influence of the hypoxia-inducible factor-1 (HIF-1) pathway inhibition on the sensitivity of HCC827 gefitinib-resistant (HCC827 GR) cells with MET amplification to gefitinib. Methods. We established HCC827 GR cell line with MET amplification and set four groups with different treatment. An MTT assay, a colony formation analysis, and a wound healing assay were performed to determine the sensitivity change of HCC827 GR cells after different treatments. HIF-1α, p-EGFR, and p-Met levels were detected with western blot. Correlations among HIF-1α, p-EGFR, and p-Met levels of HCC827 GR cells with different treatments were analyzed with Pearson’s correlation analysis. Results. HIF-1 inhibitor YC-1 enhanced the sensitivity of HCC827 GR cells to gefitinib. p-Met level was correlated with HIF-1α level, while there was no correlation between p-Met level and p-EGFR level. Conclusion. HIF-1 inhibitor YC-1 is able to reverse the acquired resistance of HCC827 GR to gefitinib, and the regulation of the HIF-1 pathway on MET may be one of the mechanisms.

Study on the HIF ‐1α regulated by glycolytic pathways and mitochondrial function in yaks of different altitudes during postmortem aging

“…Therefore, the objectives of the current study were to investigate whether hypoxia-activated HIF-1α mediated the glycolysis pathway and mechanism by which the HIF-1α-regulated glycolysis pathway affected meat tenderness of longissimus muscles in yak and beef cattle bred at different altitudes. To test our hypothesis, we used YC-1 (3-[5-hydroxymeth-2-fury1]-1-benzylindazole) to inhibit HIF-1α production during the postmortem period (Jin et al, 2021) and examined the impact of HIF-1α on meat tenderness.…”

Angiogenic activities are increased via upregulation of HIF‑1α expression in gefitinib‑resistant non‑small cell lung carcinoma cells

“…It was previously reported that HIF-1α expression was decreased in NSCLC cell lines following gefitinib treatment ( 53 , 54 ), and activation of HIF-1α in the HCC827 cell line stimulated tumorigenic activities, including proliferation and migration, even though gefitinib was administered for ~48 h ( 54 ). YC-1 enhanced the antitumor activity of gefitinib and reversed sensitivity to gefitinib in GR HCC827 cell lines ( 55 , 56 ). In the present study, the characteristics of GR NSCLC cell lines were analyzed and it was found that HIF-1α expression and angiogenic activities were increased in GR NSCLC cell lines and GR tumors compared with that in the parent NSCLC cell lines.…”

Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance

“…The HIF-1 inhibitor YC-1 was shown to resensitize the human LUAD cell line (HCC827) with acquired resistance with MET amplification to gefitinib, a first-generation EGFR TKI. The HIF-1 pathway allows cancer cells to survive in hypoxic conditions through transcriptional activation of the genes needed for survival and growth [ 176 ].…”