mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling

mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT serine 473 (S473) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase also relieves feedback inhibition of receptor tyrosine kinases (RTK), leading to subsequent phosphoinositide 3-kinase activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling.

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Rodrik-Outmezguine, V. S., et al. (2011). mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer discovery. https://doi.org/10.1158/2159-8290.CD-11-0085

@article{ROD2011,
  author       = {Rodrik-Outmezguine, V. S. and Rosen, N. and others},
  title        = {{mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling}},
  journal      = {Cancer discovery},
  year         = {2011},
  doi          = {10.1158/2159-8290.CD-11-0085},
  note         = {PMID: 22140653},
}

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Barton, O. (2026). Oliver's mTOR Atlas (record ROD2011) [Data set]. https://mtor-atlas.org/study/ROD2011/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_ROD2011,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record ROD2011},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/ROD2011/},
  doi          = {10.5281/zenodo.22059963}
}