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 of PTEN mutant cells was dependent on glutamine flux through the de novo pyrimidine synthesis pathway, which created sensitivity to 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.

Gene Expression Integration into Pathway Modules Reveals a Pan-Cancer Metabolic Landscape

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Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells

“…In our experimental models, the pathway, including DHODH itself, was primed to respond when the block in CoQ redox-cycling was removed. Inhibitors of DHODH are used in the clinic as anti-rheumatics (Olsen and Stein, 2004) and show efficacy in cancer settings either alone or in combination with anti-cancer agents (Brown et al, 2017;Mathur et al, 2017;Sykes et al, 2016;Shukla et al, 2017;Kim et al, 2017;Koundinya et al, 2018). A more effective therapeutic approach could involve intervention at the level of respiratory CIII.…”

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