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

• Published in: Cancer cell Vol. 32; no. 5; pp. 624 - 638.e5
• Main Authors: Valvezan, Alexander J., Turner, Marc, Belaid, Amine, Lam, Hilaire C., Miller, Spencer K., McNamara, Molly C., Baglini, Christian, Housden, Benjamin E., Perrimon, Norbert, Kwiatkowski, David J., Asara, John M., Henske, Elizabeth P., Manning, Brendan D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.11.2017
• Subjects: Animals; Cell Line, Tumor; HCT116 Cells; HeLa Cells; Humans; Immunoblotting; IMPDH; lymphangioleiomyomatosis; Mechanistic Target of Rapamycin Complex 1 - genetics; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; mizoribine; mTOR; mycophenolic acid; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; nucleotide synthesis; Nucleotides - genetics; Nucleotides - metabolism; rapamycin; RNA Interference; RNA, Ribosomal - genetics; RNA, Ribosomal - metabolism; TSC2; Tuberous Sclerosis - genetics; Tuberous Sclerosis - metabolism; Tuberous Sclerosis - pathology; tuberous sclerosis complex; tumor metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; tuberous sclerosis complex; mycophenolic acid; mTOR; IMPDH; TSC2; lymphangioleiomyomatosis; tumor metabolism; mizoribine; rapamycin; nucleotide synthesis
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2017.09.013

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. [Display omitted] •IMPDH inhibition selectively kills TSC2-deficient cells in an mTORC1-dependent manner•The IMPDH inhibitor mizoribine has anti-tumor effects in in vivo models of TSC•IMPDH inhibition causes replication stress and DNA damage in TSC-deficient cells•mTORC1-driven rRNA synthesis sensitizes cells to inhibition of nucleotide synthesis mTORC1 drives anabolic tumor metabolism, including ribosome biogenesis and nucleotide synthesis. Valvezan et al. show that blocking synthesis of guanine nucleotides while sustaining mTORC1 activity depletes nucleotide pools, causing DNA replication stress and apoptosis in mTORC1-driven tumor models.