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.
Background:The role of phosphorylation for regulating the Rac1 GEF PREX2 is not understood. Results: PAK phosphorylation of PREX2 downstream of PIP 3 and G␥ reduces PREX2 GEF activity. Conclusion: Second messengers can initiate negative feedback to decrease Rac1 activation through PAK phosphorylation of PREX2. Significance: PAK negative regulation of GEFs could represent a broadly utilized mechanism to attenuate Rac1 activation and its outputs.
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