論文 - 詳細
| RRC ID | 54808 |
|---|---|
| 著者 | 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. |
| タイトル | Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation. |
| ジャーナル | Cell Rep |
| 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. |
| 巻・号 | 26(2) |
| ページ | 469-482.e5 |
| 公開日 | 2019-1-8 |
| DOI | 10.1016/j.celrep.2018.12.043 |
| PII | S2211-1247(18)31973-9 |
| PMID | 30625329 |
| MeSH | Animals Cell Line, Tumor Female Fumarate Hydratase / genetics Genomics / methods Glycolysis Humans Loss of Function Mutation Mice Mice, Nude Oxidative Phosphorylation* Phosphogluconate Dehydrogenase / genetics* Synthetic Lethal Mutations* |
| IF | 7.815 |
| 引用数 | 8 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 13 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | PC-9(RCB4455) |