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Cancer Cell. 2017 Nov 13;32(5):624-638.e5. doi: 10.1016/j.ccell.2017.09.013. Epub 2017 Oct 19.

mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability.

Author information

1
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
2
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
3
Department of Genetics, Harvard Medical School, Boston, MA, USA.
4
Department of Genetics, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA.
5
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, USA.
6
Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: bmanning@hsph.harvard.edu.

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) supports proliferation through parallel induction of key anabolic processes, including protein, lipid, and nucleotide synthesis. We hypothesized that these processes are coupled to maintain anabolic balance in cells with mTORC1 activation, a common event in human cancers. Loss of the tuberous sclerosis complex (TSC) tumor suppressors results in activation of mTORC1 and development of the tumor syndrome TSC. We find that pharmacological inhibitors of guanylate nucleotide synthesis have selective deleterious effects on TSC-deficient cells, including in mouse tumor models. This effect stems from replication stress and DNA damage caused by mTORC1-driven rRNA synthesis, which renders nucleotide pools limiting. These findings reveal a metabolic vulnerability downstream of mTORC1 triggered by anabolic imbalance.

KEYWORDS:

IMPDH; TSC2; lymphangioleiomyomatosis; mTOR; mizoribine; mycophenolic acid; nucleotide synthesis; rapamycin; tuberous sclerosis complex; tumor metabolism

PMID:
29056426
PMCID:
PMC5687294
DOI:
10.1016/j.ccell.2017.09.013
[Indexed for MEDLINE]
Free PMC Article

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