Basal-shift transformation leads to EGFR therapy-resistance in human lung adenocarcinoma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard treatments for EGFR-mutant lung adenocarcinoma (LUAD).
• Therapeutic resistance to EGFR-TKIs is a significant clinical challenge, driven by various genetic alterations and unknown factors.
• Understanding resistance mechanisms is crucial for developing effective, next-generation therapies.

Purpose of the Study:

• To comprehensively investigate the molecular mechanisms underlying EGFR-TKI resistance in LUAD.
• To establish and utilize a biobank of patient-derived LUAD organoids for resistance studies.
• To identify novel resistance pathways beyond known genetic mutations.

Main Methods:

• Creation of a biobank of patient-derived EGFR-mutant lung cancer organoids from patients treated with EGFR-TKIs.
• Comprehensive molecular profiling, including single-cell analysis, of resistant organoids.
• Prospective gene engineering (NKX2-1 knockout) to validate identified pathways.

Main Results:

• Identification of a subgroup of EGFR-TKI-resistant LUAD organoids lacking known resistance mutations.
• Characterization of a
• basal-shift
• phenotype with hybrid LUAD and squamous cell carcinoma gene expression.
• NKX2-1 knockout induced basal-shift transformation and EGFR-TKI resistance.
• Basal-shift LUADs frequently showed CDKN2A/B loss and sensitivity to CDK4/6 inhibitors.

Conclusions:

• A novel basal-shift phenotype contributes to EGFR-TKI resistance in LUAD.
• The organoid biobank is a valuable resource for studying lung cancer resistance.
• Targeting CDK4/6 inhibitors may be effective for basal-shift resistant LUAD.