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 Do; Barbara 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

doi:10.1016/j.celrep.2018.12.043

Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation

Cell Rep. 2019 Jan 8;26(2):469-482.e5. doi: 10.1016/j.celrep.2018.12.043.

Authors

Yuting Sun¹, Madhavi Bandi², Timothy Lofton², Melinda Smith², Christopher A Bristow², Alessandro Carugo², Norma Rogers³, Paul Leonard³, Qing Chang², Robert Mullinax², Jing Han², Xi Shi², Sahil Seth², Brooke A Meyers², Meredith Miller², Lili Miao², Xiaoyan Ma², Ningping Feng², Virginia Giuliani², Mary Geck Do³, Barbara Czako³, Wylie S Palmer³, Faika Mseeh³, John M Asara⁴, Yongying Jiang³, Pietro Morlacchi³, Shuping Zhao², Michael Peoples², Trang N Tieu², Marc O Warmoes⁵, Philip L Lorenzi⁵, Florian L Muller⁶, Ronald A DePinho⁷, Giulio F Draetta⁸, Carlo Toniatti², Philip Jones³, Timothy P Heffernan², Joseph R Marszalek⁹

Affiliations

¹ 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.
² 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.
³ Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ 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.
⁵ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸ 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, Houston, TX 77030, USA.
⁹ 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.

PMID: 30625329
DOI: 10.1016/j.celrep.2018.12.043

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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*

Substances

Phosphogluconate Dehydrogenase
Fumarate Hydratase

Abstract

Publication types

MeSH terms

Substances

Grants and funding