Paper Chase

Paper Chase is a research database designed to offer abstracts of research articles published in journals that have a highly rated impact factor as determined by ISI Impact Factor and PageRank. Abstracts are organized by date, with the most recently published papers listed first.

Cell reports
Jan 08, 2019 26 (2) 469-482.e5
Vol. 26, Issue 2, Medline Page 469-482.e5

Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation.

Authors: Sun Y, Bandi M, Lofton T, Smith M, Bristow CA, Carugo A, Rogers N, Leonard P, Chang Q, Mullinax R, Han J, Shi X, Seth S, Meyers BA, Miller M, Miao L, Ma X, Feng N, Giuliani V, Geck Do M, Czako B, Palmer WS, Mseeh F, Asara JM, Jiang Y, Morlacchi P, Zhao S, Peoples M, Tieu TN, Warmoes MO, Lorenzi PL, Muller FL, DePinho RA, Draetta GF, Toniatti C, Jones P, Heffernan TP, Marszalek JR
Abstract:
The plasticity of a preexisting regulatory circuit compromises the effectiveness of targeted therapies, and leveraging genetic vulnerabilities in cancer cells may overcome such adaptations. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is characterized by oxidative phosphorylation (OXPHOS) deficiency caused by fumarate hydratase (FH) nullizyogosity. To identify metabolic genes that are synthetically lethal with OXPHOS deficiency, we conducted a genetic loss-of-function screen and found that phosphogluconate dehydrogenase (PGD) inhibition robustly blocks the proliferation of FH mutant cancer cells both in vitro and in vivo. Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP+/NADPH ratio to disrupt redox homeostasis. Furthermore, in the OXPHOS-proficient context, blocking OXPHOS using the small-molecule inhibitor IACS-010759 enhances sensitivity to PGD inhibition in vitro and in vivo. Together, our study reveals a dependency on PGD in OXPHOS-deficient tumors that might inform therapeutic intervention in specific patient populations.