Epiregulin confers EGFR-TKI resistance via EGFR/ErbB2 heterodimer in non-small cell lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are crucial for treating non-small cell lung cancer (NSCLC) with activating EGFR mutations.
• Mechanisms of acquired resistance to EGFR-TKIs remain incompletely understood, hindering treatment efficacy.
• Identifying novel resistance pathways is essential for improving patient outcomes.

Purpose of the Study:

• To investigate the impact of seven epidermal growth factor receptor (EGFR) ligands on EGFR-TKI sensitivity in NSCLC.
• To elucidate the role of Epiregulin (EREG) in mediating resistance to EGFR-TKIs.
• To explore the source and mechanism of EREG-induced resistance in the tumor microenvironment.

Main Methods:

• Treatment of EGFR-mutant NSCLC cells with recombinant EGFR ligands to assess cell viability, proliferation, and apoptosis.
• Manipulation of Epiregulin (EREG) expression (shRNA knockdown, overexpression) and immunofluorescence.
• Analysis of public gene expression datasets for tumor microenvironment and clinical correlations.
• Single-cell RNA sequencing to identify EREG-expressing cells within the tumor microenvironment.
• Assessment of resistance using EREG-enriched macrophage conditional medium.

Main Results:

• Epiregulin (EREG) significantly reduced sensitivity to EGFR-TKIs and correlated with poorer erlotinib response in NSCLC patients.
• EREG promoted AKT phosphorylation and inhibited TKI-induced apoptosis, dependent on ErbB2 signaling.
• EREG induced EGFR/ErbB2 heterodimer formation, irrespective of gefitinib.
• EREG's impact on TKI sensitivity was minimal when manipulated directly in cancer cells.
• Single-cell RNA sequencing identified macrophages as the primary source of EREG in the tumor microenvironment.
• Macrophage-derived EREG in conditional medium induced significant EGFR-TKI resistance.

Conclusions:

• Macrophage-derived Epiregulin (EREG) is a key mediator of acquired resistance to EGFR-TKIs in NSCLC.
• Intratumoral EREG, particularly from macrophages, represents a novel regulatory mechanism and potential biomarker for EGFR-TKI therapy.
• Targeting macrophage-produced EREG may offer a new strategy to overcome EGFR-TKI resistance in NSCLC patients.