Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation

Yuting Sun, Madhavi Bandi, Timothy Lofton, Melinda Smith, Christopher A. Bristow, Alessandro Carugo, Norma Rogers, Paul Leonard, Qing Chang, Robert Mullinax, Jing Han, Xi Shi, Sahil Seth, Brooke A. Meyers, Meredith Miller, Lili Miao, Xiaoyan Ma, Ningping Feng, Virginia Giuliani, Mary Geck DoBarbara Czako, Wylie S. Palmer, Faika Mseeh, John M. Asara, Yongying Jiang, Pietro Morlacchi, Shuping Zhao, Michael Peoples, Trang N. Tieu, Marc O. Warmoes, Philip L. Lorenzi, Florian L. Muller, Ronald A. DePinho, Giulio F. Draetta, Carlo Toniatti, Philip Jones, Timothy P. Heffernan, Joseph R. Marszalek

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)469-482.e5
JournalCell Reports
Volume26
Issue number2
DOIs
StatePublished - Jan 8 2019

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Phosphogluconate Dehydrogenase
Oxidative Phosphorylation
Genomics
Fumarate Hydratase
Mitochondrial Diseases
NADP
Cells
Leiomyomatosis
Lethal Genes
Neoplasms
Carboxylation
Glycolysis
Glutamine
Renal Cell Carcinoma
Genetic Therapy
Oxidation-Reduction
Homeostasis
Plasticity
Tumors
Genes

Keywords

  • OXPHOS
  • PGD
  • fumarate hydratase
  • functional genomics
  • hereditary leiomyomatosis renal cell carcinoma
  • metabolic vulnerability
  • pentose phosphate pathway
  • redox homeostasis
  • synthetic lethality
  • tumor metabolism

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Sun, Y., Bandi, M., Lofton, T., Smith, M., Bristow, C. A., Carugo, A., ... Marszalek, J. R. (2019). Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation. Cell Reports, 26(2), 469-482.e5. https://doi.org/10.1016/j.celrep.2018.12.043

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.

In: Cell Reports, Vol. 26, No. 2, 08.01.2019, p. 469-482.e5.

Research output: Contribution to journalArticle

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 2019, 'Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation', Cell Reports, vol. 26, no. 2, pp. 469-482.e5. https://doi.org/10.1016/j.celrep.2018.12.043
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. / Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation. In: Cell Reports. 2019 ; Vol. 26, No. 2. pp. 469-482.e5.
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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.",
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AU - Sun, Yuting

AU - Bandi, Madhavi

AU - Lofton, Timothy

AU - Smith, Melinda

AU - Bristow, Christopher A.

AU - Carugo, Alessandro

AU - Rogers, Norma

AU - Leonard, Paul

AU - Chang, Qing

AU - Mullinax, Robert

AU - Han, Jing

AU - Shi, Xi

AU - Seth, Sahil

AU - Meyers, Brooke A.

AU - Miller, Meredith

AU - Miao, Lili

AU - Ma, Xiaoyan

AU - Feng, Ningping

AU - Giuliani, Virginia

AU - Geck Do, Mary

AU - Czako, Barbara

AU - Palmer, Wylie S.

AU - Mseeh, Faika

AU - Asara, John M.

AU - Jiang, Yongying

AU - Morlacchi, Pietro

AU - Zhao, Shuping

AU - Peoples, Michael

AU - Tieu, Trang N.

AU - Warmoes, Marc O.

AU - Lorenzi, Philip L.

AU - Muller, Florian L.

AU - DePinho, Ronald A.

AU - Draetta, Giulio F.

AU - Toniatti, Carlo

AU - Jones, Philip

AU - Heffernan, Timothy P.

AU - Marszalek, Joseph R.

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KW - tumor metabolism

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