Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
The Journal of clinical investigation	127	5	2017 May 01	1631-1645	J Clin Invest

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	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
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