Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms

Area of Science:

• Oncology
• Molecular Biology
• Systems Biology

Background:

• Epidermal growth factor receptor (EGFR) mutations drive lung cancer, and resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a significant clinical challenge.
• A systems-level understanding of EGFR's molecular interactions is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To elucidate the EGFR interactome in lung cancer by analyzing protein-protein interactions and phosphorylation patterns.
• To identify a core network of proteins critical for the viability of EGFR-mutated lung cancer cells.
• To discover novel therapeutic targets and combination strategies to overcome TKI resistance.

Main Methods:

• Global analysis of protein-protein interactions and phosphorylation networks.
• Systematic perturbation of network nodes in EGFR-mutated lung cancer cells.
• Identification of core network proteins essential for cell viability.
• Drug network analysis to identify compounds targeting core network proteins.

Main Results:

• An EGFR interactome comprising 263 proteins was identified, with a 14-protein core network critical for multiple EGFR-mutated lung cancer cell lines.
• Nine core network proteins were specifically associated with the survival of EGFR-mutated lung cancer cells.
• Cells resistant to EGFR TKIs exhibited differential dependence on core network proteins.
• Midostaurin and lestaurtinib were identified as compounds that could overcome drug resistance when combined with erlotinib via direct EGFR inhibition.

Conclusions:

• Interactome mapping provides a systems-level perspective on the molecular etiology of EGFR-mutated lung cancer.
• The identified 14-protein core network represents potential therapeutic targets.
• Combination therapies involving midostaurin or lestaurtinib with erlotinib show promise for circumventing EGFR TKI resistance.