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Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation.
Sun, Yuting; Bandi, Madhavi; Lofton, Timothy; Smith, Melinda; Bristow, Christopher A; Carugo, Alessandro; Rogers, Norma; Leonard, Paul; Chang, Qing; Mullinax, Robert; Han, Jing; Shi, Xi; Seth, Sahil; Meyers, Brooke A; Miller, Meredith; Miao, Lili; Ma, Xiaoyan; Feng, Ningping; Giuliani, Virginia; Geck Do, Mary; Czako, Barbara; Palmer, Wylie S; Mseeh, Faika; Asara, John M; Jiang, Yongying; Morlacchi, Pietro; Zhao, Shuping; Peoples, Michael; Tieu, Trang N; Warmoes, Marc O; Lorenzi, Philip L; Muller, Florian L; DePinho, Ronald A; Draetta, Giulio F; Toniatti, Carlo; Jones, Philip; Heffernan, Timothy P; Marszalek, Joseph R.
Afiliación
  • Sun Y; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: ysun8@mdanderson.org.
  • Bandi M; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Lofton T; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Smith M; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Bristow CA; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Carugo A; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Rogers N; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Leonard P; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Chang Q; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Mullinax R; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Han J; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Shi X; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Seth S; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Meyers BA; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Miller M; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Miao L; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Ma X; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Feng N; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Giuliani V; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Geck Do M; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Czako B; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Palmer WS; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Mseeh F; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Asara JM; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Jiang Y; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Morlacchi P; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Zhao S; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Peoples M; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Tieu TN; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Warmoes MO; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Lorenzi PL; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Muller FL; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • DePinho RA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Draetta GF; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
  • Toniatti C; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Jones P; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Heffernan TP; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Marszalek JR; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: jrmarszalek@mdanderson.org.
Cell Rep ; 26(2): 469-482.e5, 2019 01 08.
Article en En | MEDLINE | ID: mdl-30625329
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Fosforilación Oxidativa / Fosfogluconato Deshidrogenasa / Mutaciones Letales Sintéticas Idioma: En Revista: Cell Rep Año: 2019 Tipo del documento: Article
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Fosforilación Oxidativa / Fosfogluconato Deshidrogenasa / Mutaciones Letales Sintéticas Idioma: En Revista: Cell Rep Año: 2019 Tipo del documento: Article