Blocking Ghrelin Receptor Reverses Gefitinib Resistance in Lung Cancer Cells
Background
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths, and gefitinib, an EGFR tyrosine kinase inhibitor (EGFR-TKI), is a crucial first-line treatment for patients with specific EGFR mutations. While gefitinib initially prolongs progression-free survival, nearly all advanced NSCLC patients eventually develop acquired resistance, leading to treatment failure. This study aimed to investigate if inhibiting the ghrelin receptor could overcome acquired gefitinib resistance in human lung cancer cells.
Results
The study found that the ghrelin receptor (GHSR) was overexpressed in the established HCC827/GR resistant cells compared to parental cells, accompanied by an increase in activated p-AKT and p-ERK1/2 proteins, which are crucial for cell survival and proliferation. Treatment with D-lys-3-GHRP-6 alone significantly decreased the expression of both p-AKT and p-ERK1/2 in HCC827/GR cells. Crucially, while gefitinib alone showed no significant difference compared to the control group in resistant cells, the combination therapy was highly effective. The combination of D-lys-3-GHRP-6 and gefitinib significantly inhibited cell proliferation and reduced Bcl2 protein levels, while simultaneously inducing cell apoptosis and increasing cleaved-caspase3 protein levels in both H1650 and HCC827/GR cells, effectively restoring sensitivity to gefitinib.
Why It Matters
This research highlights a novel strategy for overcoming acquired drug resistance in lung cancer, a major clinical challenge. By targeting the ghrelin receptor, this study demonstrates a potential pathway to re-sensitize resistant cancer cells to existing therapies like gefitinib. The findings suggest that ghrelin receptor antagonists could be developed as an adjuvant therapy to improve the efficacy of EGFR-TKIs in NSCLC patients. Future research should focus on in vivo studies in animal models to confirm these effects and explore optimal dosing, paving the way for potential Phase I human trials.