PTEN regulates glutamine flux to pyrimidine synthesis and sensitivity to dihydroorotate dehydrogenase inhibition

Deepti Mathur, Elias Stratikopoulos, Sait Ozturk, Nicole Steinbach, Sarah Pegno, Sarah Schoenfeld, Raymund Yong, Vundavalli V. Murty, John M. Asara, Lewis C. Cantley, Ramon Parsons

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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.

Original languageEnglish
Pages (from-to)380-390
Number of pages11
JournalCancer Discovery
Volume7
Issue number4
DOIs
StatePublished - Apr 2017

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