(613d) A Synthetic Lethal Drug Combination Mimics Glucose Deprivation–Induced Cancer Cell Death in the Presence of Glucose

Introduction: Metabolic reprogramming in cancer cells can increase their dependence on metabolic substrates such as glucose. As such, the vulnerability of cancer cells to glucose deprivation creates an attractive opportunity for therapeutic intervention. Because it is not possible to starve tumors of glucose in vivo, we sought to identify the mechanisms in glucose deprivation-induced cancer cell death and then designed inhibitor combinations to mimic glucose deprivation-induced cell death.

Results and Discussion: Using metabolomic profiling, we found that cells undergoing glucose deprivation-induced cell death exhibited dramatic accumulation of intracellular L-cysteine and its oxidized dimer, L-cystine, and depletion of the antioxidant glutathione. Building on this observation, we show that glucose deprivation–induced cell death is driven not by lack of glucose, but rather by L-cystine import. Following glucose deprivation, the import of L-cystine and its subsequent reduction to L-cysteine depleted both NADPH and glutathione pools, thereby allowing toxic accumulation of reactive oxygen species. Consistent with this model, we found that the glutamate/cystine antiporter xCT is required for increased sensitivity to glucose deprivation. Testing a drug combination that co-targeted GLUT1 (STF-31) and glutathione synthesis (BSO), we found that this combination induces synthetic lethal cell death in high xCT-expressing cell lines susceptible to glucose deprivation.

Conclusions: These results indicate that co-targeting GLUT1 and glutathione synthesis may offer a potential therapeutic approach for targeting tumors dependent on glucose for survival. Future studies will be necessary to evaluate the safety and efficacy of combined STF-31 and BSO treatment for xCT-high tumors in vivo. Taken together, our results define a new synthetic lethal drug combination that exploits the glucose addiction phenotype by mimicking glucose deprivation-induced cell death even in the presence of glucose.

References: Joly J. H., Delfarah A, Phung PS, Parrish S, Graham NA. (2020) A synthetic lethal drug combination mimics glucose deprivation–induced cancer cell death in the presence of glucose. J Biol Chem 2020;295:1350–65. https://doi.org/10.1074/jbc.RA119.011471.