title: PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition.
abstract: Metabolic changes induced by oncogenic drivers of cancer contribute to tumor growth and are attractive targets for cancer treatment. Here, we found that increased growth ofPTEN-mutant cells was dependent on glutamine flux through thede novopyrimidine synthesis pathway, which created sensitivity to the inhibition of dihydroorotate dehydrogenase, a rate-limiting enzyme for pyrimidine ring synthesis. S-phasePTEN-mutant cells showed increased numbers of replication forks, and inhibitors of dihydroorotate dehydrogenase led to chromosome breaks and cell death due to inadequate ATR activation and DNA damage at replication forks. Our findings indicate that enhanced glutamine flux generates vulnerability to dihydroorotate dehydrogenase inhibition, which then causes synthetic lethality inPTEN-deficient cells due to inherent defects in ATR activation. Inhibition of dihydroorotate dehydrogenase could thus be a promising therapy for patients withPTEN-mutant cancers.Significance:We have found a prospective targeted therapy forPTEN-deficient tumors, with efficacyin vitroandin vivoin tumors derived from different tissues. This is based upon the changes in glutamine metabolism, DNA replication, and DNA damage response which are consequences of inactivation ofPTENCancer Discov; 7(4); 380-90. ©2017 AACR.See related article by Brown et al., p. 391This article is highlighted in the In This Issue feature, p. 339.
authors.affiliation: Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.|Department of Integrated Cellular and Molecular Biology, Columbia University, New York, New York.
authors.forename: Deepti
authors.initials: D
authors.lastname: Mathur
authors.affiliation: Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Elias
authors.initials: E
authors.lastname: Stratikopoulos
authors.affiliation: Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Sait
authors.initials: S
authors.lastname: Ozturk
authors.affiliation: Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.|Department of Integrated Cellular and Molecular Biology, Columbia University, New York, New York.
authors.forename: Nicole
authors.initials: N
authors.lastname: Steinbach
authors.affiliation: Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pegno
authors.affiliation: Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Sarah
authors.initials: S
authors.lastname: Schoenfeld
authors.affiliation: Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.|Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Raymund
authors.initials: R
authors.lastname: Yong
authors.affiliation: Department of Pathology and Cell Biology and Institute for Cancer Genetics, Columbia University, New York, New York.
authors.forename: Vundavalli V
authors.initials: VV
authors.lastname: Murty
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. ramon.parsons@mssm.edu.
authors.forename: Ramon
authors.initials: R
authors.lastname: Parsons
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000096:biosynthesis*
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D005973:Glutamine; D044925:Oxidoreductases Acting on CH-CH Group Donors; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D051059:PTEN Phosphohydrolase; C030986:pyrimidine