Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation
| Autor: | Alessandro Carugo, Robert A. Mullinax, Mary Geck Do, Meredith A. Miller, Virginia Giuliani, Qing Chang, Giulio Draetta, John M. Asara, Sahil Seth, Melinda Smith, Norma Rogers, Joseph R. Marszalek, Jing Han, Philip Jones, Paul G. Leonard, Trang N. Tieu, Yongying Jiang, Brooke A. Meyers, Ronald A. DePinho, Timothy P. Heffernan, Michael Peoples, Marc O. Warmoes, Barbara Czako, Ningping Feng, Carlo Toniatti, Lili Miao, Xi Shi, Yuting Sun, Xiaoyan Ma, Florian L. Muller, Christopher A. Bristow, Wylie S. Palmer, Madhavi Bandi, Shuping Zhao, Faika Mseeh, Pietro Morlacchi, Philip L. Lorenzi, Timothy Lofton |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mice Nude Context (language use) Oxidative phosphorylation Synthetic lethality Pentose phosphate pathway Oxidative Phosphorylation General Biochemistry Genetics and Molecular Biology Fumarate Hydratase Mice 03 medical and health sciences 0302 clinical medicine Loss of Function Mutation Cell Line Tumor Animals Humans Glycolysis Phosphogluconate dehydrogenase lcsh:QH301-705.5 Chemistry Phosphogluconate Dehydrogenase Genomics Cell biology 030104 developmental biology lcsh:Biology (General) Fumarase Cancer cell Female Synthetic Lethal Mutations 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 26, Iss 2, Pp 469-482.e5 (2019) |
| ISSN: | 2211-1247 |
| Popis: | Summary: 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. : Loss-of-function genetics screen reveals a synthetically lethal interaction between OXPHOS inhibition and phosphogluconate dehydrogenase (PGD) inactivation. Sun et al. provide an example of targeting tumor metabolism in a genetically predefined context to maximize therapeutic impact and propose PGD as a therapeutic target for fumarate hydratase-deficient HLRCC. Keywords: synthetic lethality, PGD, OXPHOS, tumor metabolism, metabolic vulnerability, fumarate hydratase, redox homeostasis, functional genomics, hereditary leiomyomatosis renal cell carcinoma, pentose phosphate pathway |
| Databáze: | OpenAIRE |
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