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

Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel E, Baselga J, Guichard S, Rosen N · 2011 · Cancer discovery · Atlas ID ROD2011

What this study shows

mTOR kinase inhibition triggers feedback-dependent biphasic AKT reactivation, informing resistance.

Abstract

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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.

Read the full abstract on PubMed →

At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Cancer cells) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type	5 - Mechanistic / In Vitro
Model system	Cancer cells
Journal	Cancer discovery
Year	2011
Peer reviewed	Yes
Record last updated	2026-07-29
Source	DOI 10.1158/2159-8290.CD-11-0085 · PMID 22140653 · Free full text (PMC3227125)

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	ATP-competitive mTOR kinase inhibitors
Target	mTORC1/2 / AKT / RTK
Model	Cancer cells
Effect	In cancer cell lines, mTOR kinase inhibition causes feedback-dependent biphasic AKT regulation (transient inhibition then RTK-driven rebound)

In the Atlas

Links in the pathway map

Supports mTORC2 activates Akt/PKB
Supports ATP-competitive mTOR inhibitors inhibits mTORC1
Supports ATP-competitive mTOR inhibitors inhibits mTORC2

Learn the biology

Want to understand the biology behind this study? → Challenge 02: Why rapamycin does not switch mTORC1 off

Cite this paper

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Rodrik-Outmezguine, V. S., Chandarlapaty, S., Pagano, N. C., Poulikakos, P. I., Scaltriti, M., Moskatel, E., Baselga, J., Guichard, S., & Rosen, N. (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 Chandarlapaty, S. and Pagano, N. C. and Poulikakos, P. I. and Scaltriti, M. and Moskatel, E. and Baselga, J. and Guichard, S. and Rosen, N.},
  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},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

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}
}

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