Cancer Research

Ceramide Analog LCL768 Kills Head and Neck Cancer by Starving Mitochondria of Fumarate

Researchers at MUSC discovered that a synthetic ceramide compound called LCL768 kills head and neck squamous cell carcinoma (HNSCC) cells by triggering a self-destructive mitochondrial recycling process called mitophagy. The drug works by activating the enzyme CerS1, which produces C18-ceramide inside mitochondria. This requires DRP1 protein to be chemically modified (nitrosylated), which bridges the endoplasmic reticulum and mitochondrial membranes together. Crucially, LCL768 also depletes a metabolite called fumarate. When fumarate is low, a key recycling enzyme called PARKIN becomes activated, amplifying mitophagy. In mouse tumor models, LCL768 significantly suppressed tumor growth, and this effect was reversed when fumarate was externally supplemented, confirming fumarate depletion as a critical mechanism of action.