Cantley Lab

You are here

PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition.

TitlePTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition.
Publication TypeJournal Article
Year of Publication2017
AuthorsMathur D, Stratikopoulos E, Ozturk S, Steinbach N, Pegno S, Schoenfeld S, Yong R, Murty VV, Asara JM, Cantley LC, Parsons R
JournalCancer Discov
Volume7
Issue4
Pagination380-390
Date Published2017 Apr
ISSN2159-8290
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 PTENCancer 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.

DOI10.1158/2159-8290.CD-16-0612
Alternate JournalCancer Discov
PubMed ID28255082
Grant ListP01 CA097403 / CA / NCI NIH HHS / United States
R01 CA082783 / CA / NCI NIH HHS / United States
R01 CA155117 / CA / NCI NIH HHS / United States

Weill Cornell Medicine
Cantley Lab
Weill Cornell Medical College Meyer Cancer Center
Belfer Research Building
413 E 69th St.
Room 1362, Box 50
New York, NY 10021 Phone: (646) 962-6297