Loss of VHL and elevated expression of HIF transcription factors leads to reprogramming of tumour cell metabolism, enabling renal cell carcinoma (RCC) cells to use carbons from glutamine-derived aspartate to drive pyrimidine biosynthesis. Now, researchers show that inhibition of glutamine availability decreases aspartate availability, leading to growth inhibition of RCC cells. Moreover, glutaminase 1 (GLS1) inhibition increases oxidative stress, leading to DNA replication stress and growth arrest. “These findings led us to combine a GLS1 inhibitor with an inhibitor of DNA repair enzymes — in this case, a poly(ADPribose) polymerase (PARP) inhibitor — to achieve therapeutic synergism,” explains Othon Iliopoulos. “In other words, we discovered how targeting a metabolic pathway renders VHL-deficient cancer cells sensitive to DNA repair mechanisms.” Iliopoulos hopes to take their findings directly to a clinical trial. “We now plan to treat patients with renal and other HIF-expressing cancers with this novel combination of GLS1 and PARP inhibitors,” he explains.

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