Targeting UGCG Overcomes Resistance to Lysosomal Autophagy Inhibition

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Lysosomal autophagy inhibition (LAI) can enhance cancer therapy but often encounters tumor regrowth.
• Understanding the mechanisms of LAI resistance is crucial for improving cancer treatment outcomes.

Purpose of the Study:

• To elucidate the mechanisms of resistance to lysosomal autophagy inhibition (LAI) in cancer therapy.
• To identify novel therapeutic targets for overcoming LAI resistance.

Main Methods:

• Proteomics, immunoblotting, and lipidomics were used to analyze cancer cell lines.
• Enzyme activity assays and drug inhibition studies were performed.
• Tumor growth and survival were evaluated in preclinical cancer models.

Main Results:

• LAI induced significant alterations in lipid metabolism, including increased cholesterol, sphingolipids, and glycosphingolipids, associated with GM1+ membrane microdomains (GMM).
• Inhibition of cholesterol/sphingolipid metabolism, particularly UDP-glucose ceramide glucosyltransferase (UGCG), synergistically enhanced LAI cytotoxicity.
• High UGCG expression correlated with shorter disease-specific survival in melanoma patients.
• The FDA-approved UGCG inhibitor eliglustat combined with LAI demonstrated significant tumor growth inhibition and improved survival in preclinical models.

Conclusions:

• UGCG-dependent lipid remodeling drives resistance to LAI in cancer.
• Targeting UGCG represents a promising strategy to enhance LAI efficacy in cancer therapy.
• Clinical trials combining LAI with UGCG inhibitors are warranted for various cancers.