An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1*

By C. Thoreen, S. A. Kang, J. Chang, Qingsong Liu, Jianming Zhang, Yi Gao, L. Reichling, Taebo Sim, David M. Sabatini, Nathanael S. Gray. Journal of Biological Chemistry, 2009

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The mammalian target of rapamycin (mTOR) kinase is the catalytic subunit of two functionally distinct complexes, mTORC1 and mTORC2, that coordinately promote cell growth, proliferation, and survival. Rapamycin is a potent allosteric mTORC1 inhibitor with clinical applications as an immunosuppressant and anti-cancer agent. Here we find that Torin1, a highly potent and selective ATP-competitive mTOR inhibitor that directly inhibits both complexes, impairs cell growth and proliferation to a far greater degree than rapamycin. Surprisingly, these effects are independent of mTORC2 inhibition and are instead because of suppression of rapamycin-resistant functions of mTORC1 that are necessary for cap-dependent translation and suppression of autophagy. These effects are at least partly mediated by mTORC1-dependent and rapamycin-resistant phosphorylation of 4E-BP1. Our findings challenge the assumption that rapamycin completely inhibits mTORC1 and indicate that direct inhibitors of mTORC1 kinase activity may be more successful than rapamycin at inhibiting tumors that depend on mTORC1.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a1ba8bf49ec92694da91107dcbfa1769b046a7e8

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Citations in the corpus

Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. (2011, background): “This question can be addressed using selective TORC1/2 inhibitors (Chresta et al., 2010; Thoreen et al., 2009).”
The Role of Autophagy in Cancer: Therapeutic Implications (2011, background): “In preclinical studies, dual inhibitors of mTORC1 and mTORC2 showed antitumor activity (55–57) and were shown to be more potent inducers of autophagy compared to mTORC1 inhibitors (58, 59).”
Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “Moreover, the potent and ATP-competitive mTOR inhibitor repressed mRNA translation and suppressed cellular proliferation.(80) Another study has revealed that mRNAs that are controlled by mTORC1 are 5’ terminal oligopyrimidine (TOP) motifs.”
mTOR signaling in growth control and disease (2012, positive): “groups have developed small molecules that directly inhibit mTOR kinase activity (Chresta et al., 2010; Feldman et al., 2009; Garcı́a-Martı́nez et al., 2009; Thoreen et al., 2009; Yu et al., 2009).”
The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis (2012, positive): “Therefore, we also tested the effect of torin 1, a more recently developed ATP-competitive inhibitor that blocks the activity of mTOR towards all substrates (31) and observed strong nuclear translocation of TFEB, enhanced lysosome association (see also Fig.”