VDR Decrease Enhances the Efficacy of 1,25-Dihydroxyvitamin D3 Inhibiting Gefitinib Resistance by Regulating...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Gefitinib, a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is a first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC).
• Acquired resistance to EGFR-TKIs presents a significant challenge, necessitating novel therapeutic strategies.
• The role of Vitamin D Receptor (VDR) in mediating this resistance is not fully understood.

Purpose of the Study:

• To investigate the role of VDR in the development of acquired resistance to EGFR-TKIs in NSCLC.
• To explore the therapeutic potential of targeting VDR in overcoming gefitinib resistance.

Main Methods:

• Analysis of VDR expression in The Cancer Genome Atlas (TCGA) database and gefitinib-resistant NSCLC cell lines.
• Assessment of cell proliferation and apoptosis using MTT assays, colony formation assays, and flow cytometry.
• Evaluation of VDR, EGFR, and FASN expression via immunofluorescence, qPCR, and Western blotting.
• In vivo studies using xenograft models in mice to assess the effects of VDR modulation and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment.

Main Results:

• VDR was significantly upregulated in EGFR-TKI-resistant NSCLC cells, correlating with poor patient prognosis.
• VDR knockdown inhibited proliferation and tumor growth, reducing gefitinib resistance, while VDR overexpression enhanced resistance.
• A positive feedback loop involving VDR, EGFR, and FASN was identified, with VDR knockdown downregulating EGFR and FASN.
• 1,25(OH)2D3 treatment increased VDR but decreased EGFR and FASN; VDR knockdown potentiated 1,25(OH)2D3's effect in overcoming gefitinib resistance.

Conclusions:

• VDR drives NSCLC resistance to EGFR-TKIs by regulating EGFR and FASN expression through a positive feedback loop.
• Targeting VDR, particularly in combination with 1,25(OH)2D3, represents a promising strategy to overcome gefitinib resistance.
• Synergistic downregulation of EGFR and FASN by VDR knockdown and 1,25(OH)2D3 offers a potential therapeutic approach for resistant NSCLC.