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Ref Type | Journal Article | ||||||||||||
PMID | (28346230) | ||||||||||||
Authors | Okazaki A, Gameiro PA, Christodoulou D, Laviollette L, Schneider M, Chaves F, Stemmer-Rachamimov A, Yazinski SA, Lee R, Stephanopoulos G, Zou L, Iliopoulos O | ||||||||||||
Title | Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers. | ||||||||||||
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Abstract Text | Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate (αKG). Glutamine can also generate aspartate, the carbon source for pyrimidine biosynthesis, and glutathione for redox balance. Here we have shown that VHL-/- RCC cells rely on RC-derived aspartate to maintain de novo pyrimidine biosynthesis. Glutaminase 1 (GLS1) inhibitors depleted pyrimidines and increased ROS in VHL-/- cells but not in VHL+/+ cells, which utilized glucose oxidation for glutamate and aspartate production. GLS1 inhibitor-induced nucleoside depletion and ROS enhancement led to DNA replication stress and activation of an intra-S phase checkpoint, and suppressed the growth of VHL-/- RCC cells. These effects were rescued by administration of glutamate, αKG, or nucleobases with N-acetylcysteine. Further, we observed that the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib synergizes with GLS1 inhibitors to suppress the growth of VHL-/- cells in vitro and in vivo. This work describes a mechanism that explains the sensitivity of RCC tumor growth to GLS1 inhibitors and supports the development of therapeutic strategies for targeting VHL-deficient RCC. |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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VHL loss | renal cell carcinoma | sensitive | BPTES + Olaparib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of BPTES and Lynparza (olaparib) resulted in a synergistic effect, demonstrating growth inhbition of VHL-deficient renal cell carcinoma cells in culture (PMID: 28346230). | 28346230 |
VHL loss | renal cell carcinoma | sensitive | BPTES | Preclinical - Cell culture | Actionable | In a preclinical study, VHL-deficient renal cell carcinoma cells demonstrated growth inhibition and suppression of DNA synthesis in culture when treated with BPTES (PMID: 28346230). | 28346230 |
VHL loss | renal cell carcinoma | sensitive | Olaparib + Telaglenastat | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of CB-839 and Lynparza (olaparib) resulted in a synergistic effect, demonstrating greater reduction in tumor volume compared to either agent alone in renal carcinoma cell xenograft models deficient for VHL (PMID: 28346230). | 28346230 |
VHL loss | renal cell carcinoma | sensitive | Telaglenastat | Preclinical - Cell culture | Actionable | In a preclinical study, VHL-deficient renal cell carcinoma cells demonstrated growth inhibition in culture when treated with CB-839 (PMID: 28346230). | 28346230 |