PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition
Open accessPublished version of a preprint
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 of PTEN-mutant cells was dependent on glutamine flux through the de novo pyrimidine synthesis pathway, which created sensitivity to the inhibition of dihydroorotate dehydrogenase, a rate-limiting enzyme for pyrimidine ring synthesis. S-phase PTEN-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 in PTEN-deficient cells due to inherent defects in ATR activation. Inhibition of dihydroorotate dehydrogenase could thus be a promising therapy for patients with PTEN-mutant cancers. Significance: We have found a prospective targeted therapy for PTEN-deficient tumors, with efficacy in vitro and in vivo in 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 of PTEN. Cancer Discov; 7(4); 380–90. ©2017 AACR. See related article by Brown et al., p. 391. This article is highlighted in the In This Issue feature, p. 339
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PTEN-deficient cells, which have active mTOR signaling, are more sensitive to DHODH inhibition by brequinar and leflunomide.
“PTEN-deficient cells, which have active mTOR signaling, are more sensitive to inhibition of DHODH by brequinar and leflunomide (Mathur et al., 2017).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Mathur et al., 2017
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 34 · Cited by 139
Research works printed but not linked: 1
- [34]ANITA SC Finnegan A Jiang X Gebel H Sankary HN Foster P Leflunomide, A Novel Immunosuppressive Agent: The Mechanism of Inhibition of T Cell Proliferation Transplantation 1993 55 6 1361 6 8390735
- Authors
- Mathur, D., Stratikopoulos, E., Ozturk, S., Steinbach, N., Pegno, S., Schoenfeld, S., Yong, R., Murty, V. V., Asara, J. M., Cantley, L. C., & Parsons, R.
- Affiliations
- Tisch Cancer Institute (US)
- 1Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
- Columbia University (US)
- Beth Israel Deaconess Medical Center (US)
- Weill Cornell Medicine (US)
- Venue
- Cancer Discovery
- Published
- 2017-04-01
- Volume
- 7
- Issue
- 4
- Pages
- 380-390
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC5562025
- OpenAlex
- W2590621600
- Cited by
- 139
- References
- 34
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 12 · 2023: 18 · 2022: 19 · 2021: 14 · 2020: 19 · 2019: 15 · 2018: 14 · 2017: 2
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Columbia Academic Commons (Columbia University)
- Funders
- NIH (R01CA082783, R01CA155117, and P01CA97403, 5P01CA120964 and 5P30CA006516)
- Breast Cancer Research Foundation (R01 GM041890)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- PTEN, glutamine metabolism, de novo pyrimidine biosynthesis, dihydroorotate dehydrogenase inhibition, synthetic lethality, DNA damage response, chromosome breakage, cancer metabolism, targeted therapy
- MeSH terms
- Dihydroorotate Dehydrogenase, Animals, DNA Damage, DNA Replication, Enzyme Inhibitors, Fibroblasts, Glutamine, Humans, Neoplasms, Pyrimidines, Oxidoreductases Acting on CH-CH Group Donors, PTEN Phosphohydrolase, Mice, Metabolic Networks and Pathways, Gene Knockout Techniques, Ataxia Telangiectasia Mutated Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
