Overview

• Preclinical studies show that combining PIKfyve inhibitors with KRAS-MAPK pathway blockers eliminates pancreatic tumors in advanced mouse and human models.
• PIKfyve inhibition disrupts lysosomal lipid recycling, forcing cancer cells to rely on de novo lipid synthesis for survival.
• Blocking PIKfyve creates a synthetic lethality with enzymes involved in fatty acid, sphingolipid, and cholesterol biosynthesis, making these cells highly vulnerable.
• KRAS-MAPK signaling is activated as a compensatory mechanism under PIKfyve inhibition, but dual targeting of both pathways prevents tumor adaptation.
• Next steps include in vivo safety profiling, exploring immune system recruitment, and preparing for early-phase clinical trials to validate this approach.