Allyson O'Donnell,

Summary

Mechanisms of Glycolytic Inhibitor Resistance

Cancer cells rely heavily on glycolysis — the conversion of glucose into energy — to fuel their growth, a phenomenon known as the Warburg effect. This dependency creates a therapeutic opportunity: drugs that block glycolysis, such as the glucose analog 2-deoxyglucose (2DG), can selectively starve cancer cells. However, these drugs have had limited clinical success because resistance develops rapidly.

Using budding yeast as a genetically tractable model, we discovered that 2DG works by triggering the removal of glucose transporters from the cell surface, cutting off the cell's fuel supply. Every resistance pathway we identified preserved transporter availability, restoring glucose access. We have since shown that these resistance mechanisms extend to other glycolytic inhibitors and involve broad remodeling of the cell's membrane proteome. We are now translating these findings into breast cancer and glioblastoma cell lines to determine whether the same mechanisms operate in human cancers — and how they might be overcome.