PKCδ-mediated SGLT1 upregulation confers the acquired resistance of NSCLC to EGFR TKIs

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard treatments for non-small cell lung cancer (NSCLC).
• Acquired resistance to EGFR TKIs is a major clinical challenge.
• Reduced glucose uptake is associated with EGFR TKI anti-tumor effects.

Purpose of the Study:

• To investigate the role of sodium/glucose co-transporter 1 (SGLT1) in acquired EGFR TKI resistance in NSCLC.
• To explore SGLT1 as a potential therapeutic target to overcome EGFR TKI resistance.

Main Methods:

• Correlation analysis of SGLT1 expression with clinical outcomes in NSCLC patients treated with EGFR TKIs.
• In vitro and in vivo experiments to assess the effect of SGLT1 blockade on NSCLC cells.
• Mechanistic studies involving protein interactions and phosphorylation.

Main Results:

• Upregulation of active SGLT1 was identified as a mechanism conferring acquired EGFR TKI resistance.
• Increased SGLT1 expression correlated with poorer clinical outcomes in NSCLC patients.
• SGLT1 blockade effectively overcame EGFR TKI resistance in vitro and in vivo by reducing glucose uptake.
• SGLT1 protein stabilization was mediated by interaction with PKCδ-phosphorylated EGFR in resistant cells.

Conclusions:

• The PKCδ/EGFR axis-driven SGLT1 upregulation is a critical mechanism of acquired resistance to EGFR TKIs in NSCLC.
• Co-targeting PKCδ and SGLT1 presents a promising strategy to enhance EGFR TKI efficacy in NSCLC patients.