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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.
Journal The Journal of clinical investigation
Vol 127
Issue 5
Date 2017 May 01
URL
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 Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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