@article{1f0b4453f6c9477e9f402335e14d1ca2,
title = "Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation",
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.",
keywords = "OXPHOS, PGD, fumarate hydratase, functional genomics, hereditary leiomyomatosis renal cell carcinoma, metabolic vulnerability, pentose phosphate pathway, redox homeostasis, synthetic lethality, tumor metabolism",
author = "Yuting Sun and Madhavi Bandi and Timothy Lofton and Melinda Smith and Bristow, {Christopher A.} and Alessandro Carugo and Norma Rogers and Paul Leonard and Qing Chang and Robert Mullinax and Jing Han and Xi Shi and Sahil Seth and Meyers, {Brooke A.} and Meredith Miller and Lili Miao and Xiaoyan Ma and Ningping Feng and Virginia Giuliani and {Geck Do}, Mary and Barbara Czako and Palmer, {Wylie S.} and Faika Mseeh and Asara, {John M.} and Yongying Jiang and Pietro Morlacchi and Shuping Zhao and Michael Peoples and Tieu, {Trang N.} and Warmoes, {Marc O.} and Lorenzi, {Philip L.} and Florian Muller and DePinho, {Ronald A.} and Draetta, {Giulio F.} and Carlo Toniatti and Philip Jones and Heffernan, {Timothy P.} and Marszalek, {Joseph R.}",
note = "Funding Information: The authors thank Dr. Linehan at NIH for providing the UOK262 and UOK262-FH cells; Dr. H. Ying for reading the manuscript critically; the Department of Veterinary Medicine & Surgery at MD Anderson Cancer Center (MDACC) for mouse husbandry and care; the flow cytometry lab at MDACC for help with flow cytometry; the research histopathology facility at MDACC for histology service; and all members at the Institute for Applied Cancer Science at MDACC for discussions. F.L.M. was supported by research scholar grants RSG-15-145-01-CDD from the American Cancer Society, CDP SPORE P50CA127001-07 from the NIH, and RP140612 from the Cancer Prevention Research Institute of Texas (CPRIT). The Proteomics and Metabolomics Core Facility at MDACC is supported by CPRIT grant RP130397, NIH grant 1S10OD012304-01, and NIH/NCI grant P30CA016672. Funding Information: The authors thank Dr. Linehan at NIH for providing the UOK262 and UOK262-FH cells; Dr. H. Ying for reading the manuscript critically; the Department of Veterinary Medicine & Surgery at MD Anderson Cancer Center (MDACC) for mouse husbandry and care; the flow cytometry lab at MDACC for help with flow cytometry; the research histopathology facility at MDACC for histology service; and all members at the Institute for Applied Cancer Science at MDACC for discussions. F.L.M. was supported by research scholar grants RSG-15-145-01-CDD from the American Cancer Society , CDP SPORE P50CA127001-07 from the NIH , and RP140612 from the Cancer Prevention Research Institute of Texas (CPRIT). The Proteomics and Metabolomics Core Facility at MDACC is supported by CPRIT grant RP130397 , NIH grant 1S10OD012304-01 , and NIH/NCI grant P30CA016672 . Publisher Copyright: {\textcopyright} 2018 The Author(s)",
year = "2019",
month = jan,
day = "8",
doi = "10.1016/j.celrep.2018.12.043",
language = "English (US)",
volume = "26",
pages = "469--482.e5",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",
}