EGFR inhibitor-driven endoplasmic reticulum stress-mediated injury on intestinal epithelial cells

Area of Science:

• Oncology
• Molecular Biology
• Gastroenterology

Background:

• Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are crucial in treating non-small-cell lung cancer.
• Diarrhea is a frequent and dose-limiting adverse effect of EGFR-TKI therapy.
• Understanding the mechanisms behind EGFR-TKI-induced diarrhea is essential for improving patient outcomes.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying diarrhea induced by EGFR-TKIs.
• To compare the cytotoxic effects of gefitinib and icotinib on intestinal epithelial cells.
• To identify potential therapeutic strategies for mitigating EGFR-TKI-associated gastrointestinal toxicity.

Main Methods:

• Comparative analysis of gefitinib and icotinib on intestinal epithelial cells (IEC-6).
• Assessment of cell proliferation (MTT assay), cytokine expression (real-time PCR), cell cycle and apoptosis (flow cytometry), and protein levels (Western blot).

Main Results:

• Both gefitinib and icotinib induced cytotoxicity, inhibiting proliferation and promoting apoptosis in IEC-6 cells.
• EGFR-TKIs caused G0/G1 cell cycle arrest, altered cell adhesion molecule expression, and increased pro-inflammatory cytokines (IL-6, IL-25).
• A significant endoplasmic reticulum (ER) stress response, involving PERK and XBP-1 pathways, was observed, leading to ER-mediated cell death. Gefitinib exhibited greater cytotoxicity than icotinib.

Conclusions:

• EGFR-TKI-induced diarrhea is linked to direct cytotoxicity on intestinal epithelial cells via cell cycle arrest, altered adhesion, inflammation, and ER stress.
• Icotinib demonstrates reduced cytotoxicity compared to gefitinib, positioning it as a potentially safer therapeutic option for non-small-cell lung cancer patients.
• These findings have significant clinical implications for managing EGFR-TKI therapy and improving patient tolerance.