Cholesterol promotes EGFR-TKIs resistance in NSCLC by inducing EGFR/Src/Erk/SP1 signaling-mediated ERRα re-expression

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improve survival in advanced non-small cell lung cancer (NSCLC) with EGFR mutations.
• Acquired resistance to EGFR-TKIs is a significant clinical challenge, limiting their long-term efficacy.
• Understanding resistance mechanisms is crucial for developing effective treatment strategies.

Purpose of the Study:

• To elucidate a common molecular mechanism driving acquired resistance to EGFR-TKIs in NSCLC.
• To identify potential therapeutic targets to overcome EGFR-TKI resistance.
• To investigate the role of cholesterol metabolism and ERRα in EGFR-TKI resistance.

Main Methods:

• Established EGFR-TKI-resistant NSCLC cell lines and confirmed resistance via MTT assay.
• Quantified cellular cholesterol levels and assessed its in vivo impact on NSCLC growth.
• Utilized immunofluorescence, co-immunoprecipitation, luciferase reporter assays, and chromatin immunoprecipitation to dissect molecular pathways.

Main Results:

• EGFR-TKI resistance is characterized by cholesterol accumulation in lipid rafts, promoting EGFR/Src signaling reactivation.
• This signaling cascade leads to SP1 nuclear translocation and subsequent re-expression of ERRα, a target gene of SP1.
• Re-expressed ERRα promotes cancer cell proliferation by regulating reactive oxygen species (ROS) detoxification.
• Lovastatin (cholesterol-lowering) and XCT790 (ERRα inverse agonist) effectively reversed gefitinib and osimertinib resistance in vitro and in vivo.

Conclusions:

• The cholesterol/EGFR/Src/Erk/SP1 axis-induced ERRα re-expression drives the survival of resistant NSCLC cells.
• Reducing cholesterol levels and downregulating ERRα show promise as adjuvant therapies for NSCLC.
• Targeting cholesterol metabolism and ERRα offers a potential strategy to overcome EGFR-TKI resistance.