FBXW7 deletion contributes to lung tumor development and confers resistance to gefitinib therapy

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Gefitinib (an EGFR-TKI) effectively treats EGFR-mutated NSCLC but acquired resistance limits efficacy.
• The tumor suppressor FBXW7's role in EGFR-TKI resistance in NSCLC is largely unstudied.
• FBXW7 loss is implicated in chemosensitivity modulation across various cancers.

Purpose of the Study:

• To investigate the role of FBXW7 in non-small-cell lung cancer (NSCLC) progression and resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs).
• To explore the therapeutic potential of combining gefitinib with rapamycin in FBXW7-deficient NSCLC models.

Main Methods:

• Analysis of The Cancer Genome Atlas (TCGA) data for FBXW7 deletion frequency and expression in lung cancer.
• FBXW7 knockdown in NSCLC cell lines to assess effects on epithelial-mesenchymal transition (EMT), migration, and invasion.
• Evaluation of gefitinib resistance in FBXW7-silenced cells and the impact of rapamycin treatment.
• Xenograft mouse models to study tumorigenesis and gefitinib resistance with FBXW7 knockdown.

Main Results:

• FBXW7 deletion is frequent in lung adenocarcinomas and squamous cell carcinomas, correlating with reduced FBXW7 mRNA and poor patient survival.
• FBXW7 knockdown promoted EMT, migration, and invasion in NSCLC cells.
• Silencing FBXW7 induced gefitinib resistance, which was reversed by rapamycin.
• FBXW7 knockdown enhanced tumorigenesis and gefitinib resistance in vivo, with combination therapy suppressing tumor growth.

Conclusions:

• Loss of FBXW7 significantly contributes to NSCLC progression and acquired resistance to gefitinib (EGFR-TKI).
• Rapamycin can overcome gefitinib resistance in FBXW7-deficient NSCLC.
• Combination therapy with gefitinib and rapamycin presents a promising strategy for treating gefitinib-resistant NSCLC.