(176s) Development of Synthetic Lethal Drug Combinations Targeting Metabolic Vulnerabilities in Glioblastoma Cells

Cancer cells undergo metabolic reprogramming to satisfy increased demand for biosynthetic precursors to sustain rapid proliferation. The consequences of metabolic reprogramming can include an increased dependence on metabolic substrates such as glucose for survival. As such, the vulnerability of cancer cells to glucose deprivation presents an attractive opportunity for therapeutic intervention. However, because it is not possible to completely starve cancer cells of glucose in vivo, we sought to identify therapeutic approaches that would mimic glucose deprivation-induced cell death. Using mass spectrometry-based metabolomics, we found that glucose deprivation-sensitive cells exhibited a dramatic accumulation of L-cystine and L-cysteine and depletion of glutathione following glucose deprivation. Surprisingly, we found that activity of the rate limiting enzyme for glutathione synthesis, glutamate-cysteine ligase, increased in response to glucose deprivation, suggesting no blockage in glutathione synthesis. Building upon this observation, we found that import of L-cystine from the glutamate/cystine antiporter, xCT/SLC7A11, induced reactive oxygen species-mediated cell death in glucose deprived cancer cells. To identify druggable glycolytic nodes to mimic glucose deprivation-induced cell death, we integrated data from the Cancer Dependency Map (DEPMAP) and found that GLUT1 dependency increased with increasing expression of xCT/SLC7A11. Therefore, we tested a drug combination co-targeting GLUT1 and glutathione synthesis and found that these drugs induced synthetic lethal cell death. These findings demonstrate the systems biology-driven discovery of novel synthetic lethal treatment strategies targeting metabolic vulnerabilities in cancer cells.