AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity
Open accessAbstract
Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. We now show that AKT inhibition induces the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs). In a wide spectrum of tumor types, inhibition of AKT induces a conserved set of RTKs, including HER3, IGF-1R, and insulin receptor. This is in part due to mTORC1 inhibition and in part secondary to a FOXO-dependent activation of receptor expression. PI3K-AKT inhibitors relieve this feedback and activate RTK signaling; this may attenuate their antitumor activity. Consistent with this model, we find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone.
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Activation of FOXO transcription factors or downregulation of MYC can trigger feedback activation of RTK transcription following inhibition of PI3K/AKT or MEK pathways.
“Furthermore, early studies have shown that activation of FOXO transcription factors or downregulation of MYC can trigger feedback activation of RTK transcription following inhibition of the PI3K/AKT or MEK pathways,27,28”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [27]
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- Authors
- Chandarlapaty, S., Sawai, A., Scaltriti, M., Rodrik-Outmezguine, V., Grbovic-Huezo, O., Serra, V., Majumder, P. K., Baselga, J., & Rosen, N.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Vall d'Hebron Hospital Universitari (ES)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Rosen, Neal
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 19
- Issue
- 1
- Pages
- 58-71
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3025058
- OpenAlex
- W2155228605
- Cited by
- 967
- References
- 1
- Citations by year
- 2026: 31 · 2025: 30 · 2024: 35 · 2023: 40 · 2022: 37 · 2021: 52 · 2020: 55 · 2019: 52 · 2018: 59 · 2017: 58 · 2016: 86 · 2015: 95 · 2014: 110 · 2013: 107 · 2012: 75
- FWCI
- 43.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 928 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Breast Cancer Research Foundation
- European Research Council (AdG09 250244)
- National Institutes of Health (K08-CA134833)
- 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 inhibition, PI3K/Akt signaling, receptor tyrosine kinase, negative feedback signaling, mTORC1, FOXO, HER3, IGF-1 receptor, insulin receptor, combination therapy, anticancer activity
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Gefitinib, Lapatinib, Animals, Benzylamines, Breast Neoplasms, Carcinoma, Non-Small-Cell Lung, Drug Therapy, Combination, Female, Humans, Mice, Nude, Models, Biological, Neoplasms, Phosphorylation, Promoter Regions, Genetic, Protein Binding, Proteins, Quinazolines, Quinoxalines, Receptor, Insulin, Signal Transduction, Up-Regulation, Gene Expression, Gene Expression Regulation, Neoplastic, Receptor, IGF Type 1, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Receptor Protein-Tyrosine Kinases, Receptor, ErbB-3, Xenograft Model Antitumor Assays, Feedback, Physiological, RNA, Small Interfering, Cell Line, Tumor, Multiprotein Complexes, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Mice, Forkhead Transcription Factors, TOR Serine-Threonine Kinases
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