2173 - GDPD5-CD55-EGFR Competitive Binding Axis, Radioresistance, and Lipid Accumulation in Rectal Cancer

Purpose/Objective(s): Resistance to neoadjuvant chemoradiotherapy (nCRT) in rectal cancer adversely affects patient survival rates. This study aims to explore the potential role of dysregulated lipid metabolism in promoting radioresistance through the GDPD5-CD55-EGFR signaling axis and to assess the viability of targeting GDPD5 as a therapeutic intervention.

Materials/Methods: Genes related to lipid metabolism (LMRGs) were identified using the Molecular Signatures Database (MSigDB) and analyzed within the GSE68204 cohort, which includes 59 patients with rectal cancer. Radioresistant cell lines (HCT116/R, DLD-1/R), xenograft models, and patient-derived organoids (PDOs) were developed for this study. Key regulatory genes were identified using support vector machine-recursive feature elimination (SVM-RFE), random forest (RF), and least absolute shrinkage and selection operator (LASSO) algorithms. Mechanistic investigations involved GDPD5 silencing, co-immunoprecipitation (Co-IP), molecular docking, immunofluorescence, and functional assays such as colony formation and Oil Red O/BODIPY staining. Clinical validation was conducted through immunohistochemistry (IHC) on tissue samples from 20 patients.

Results: Radioresistant rectal cancer demonstrated a marked accumulation of lipids. Through multi-algorithm analysis, GDPD5 was identified as the primary regulatory factor (AUC=0.87). The silencing of GDPD5 led to a reduction in lipid droplets, suppression of fatty acid synthase (FASN), enhancement of adipose triglyceride lipase (ATGL) expression, and increased radiosensitivity both in vitro and in vivo. Mechanistically, GDPD5 competitively binds to CD55 at the LYS-161/GLN-212 residues, thereby displacing epidermal growth factor receptor (EGFR) from the cell membrane and facilitating its translocation to the nucleus. Within the nucleus, EGFR suppresses p53 activity, resulting in lipid accumulation and radioresistance. Clinical samples corroborated that high GDPD5 expression coupled with low CD55 expression was associated with EGFR nuclear localization. PDOs exhibiting elevated GDPD5 levels demonstrated increased radioresistance.

Conclusion:

GDPD5 contributes to radioresistance by disrupting the CD55-EGFR interaction, thereby promoting EGFR nuclear translocation and p53 suppression, which in turn induces lipid accumulation. Targeting the GDPD5-CD55-EGFR axis offers a promising strategy to overcome resistance to nCRT in rectal cancer.