mTOR Kinase Inhibition Causes Feedback-Dependent Biphasic Regulation of AKT Signaling
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Abstract
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. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound suppression of mTORC1 and accumulation of activated AKT phosphorylated on T308, but not S473. Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in substantial cell death and tumor regression in vivo. These findings reveal the adaptive capabilities of oncogenic signaling networks and the limitations of monotherapy for inhibiting feedback-regulated pathways. Significance: The results of this study show the adaptive capabilities of oncogenic signaling networks, as AKT signaling becomes reactivated through a feedback-induced AKT species phosphorylated on T308 but lacking S473. The addition of RTK inhibitors can prevent this reactivation of AKT signaling and cause profound cell death and tumor regression in vivo, highlighting the possible need for combinatorial approaches to block feedback-regulated pathways. Cancer Discovery; 1(3); 248–59. © 2011 AACR. Read the Commentary on this article by Keniry and Parsons, p. 203 This article is highlighted in the In This Issue feature, p. 189
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Prolonged use of mTOR inhibitors may cause adverse effects.
“prolonged use of mTOR inhibitors may cause adverse effects (Rodrik-Outmezguine et al., 2011).”
From Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits (2014) · cites this paper as Rodrik-Outmezguine et al., 2011
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- Authors
- Rodrik-Outmezguine, V. S., Chandarlapaty, S., Pagano, N. C., Poulikakos, P. I., Scaltriti, M., Moskatel, E., Baselga, J., Guichard, S., & Rosen, N.
- Affiliations
- AstraZeneca (United Kingdom) (GB)
- Memorial Sloan Kettering Cancer Center (US)
- Authors' Affiliations: 1Program in Molecular Pharmacology and Chemistry and 2Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; 3Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts; 4AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom
- Corresponding author
- Rosen, Neal
- ORCID
- Venue
- Cancer Discovery
- Published
- 2011-08-01
- Volume
- 1
- Issue
- 3
- Pages
- 248-259
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3227125
- OpenAlex
- W1965626427
- Cited by
- 442
- References
- 44
- Citations by year
- 2026: 18 · 2025: 19 · 2024: 9 · 2023: 21 · 2022: 18 · 2021: 24 · 2020: 24 · 2019: 24 · 2018: 30 · 2017: 36 · 2016: 39 · 2015: 48 · 2014: 60 · 2013: 47 · 2012: 21
- FWCI
- 17.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5k08ca134833-02)
- National Cancer Institute (P01CA094060, K08-CA134833, P50CA086438, T32CA062948, P50CA092629)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Akt signaling, mTORC1, mTORC2, feedback regulation, receptor tyrosine kinase signaling, phosphatidylinositol 3-kinase, adaptive resistance, combination therapy, tumor regression, cell death
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Female, Humans, Mice, Nude, Morpholines, Phosphorylation, Proteins, Transcription Factors, Signal Transduction, Cell Death, Phosphatidylinositol 3-Kinases, Receptor Protein-Tyrosine Kinases, Cell Line, Tumor, Multiprotein Complexes, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Mice, TOR Serine-Threonine Kinases
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