ArticleOncotarget2015
AKT inhibition overcomes rapamycin resistance by enhancing the repressive function of PRAS40 on mTORC1/4E-BP1 axis.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 61 citations in OpenAlex.
- Role of the PI3K/AKT signaling pathway in regulating gene expression in rheumatoid arthritis (Review).Molecular medicine reports · 2026Review
- Thrombomodulin is essential for recombinant Fc-fusion protein production in Chinese hamster ovary cells via multiple signaling pathways.Journal of biological engineering · 2025Article
- Phosphatidylinositol 3-kinase and mechanistic target of rapamycin dualinhibitor, VDC597, as a therapeutic agent for canine osteosarcoma.The Journal of pharmacology and experimental therapeutics · 2025Article
- Breast Cancer Cell Line-Specific Responses to Insulin: Effects on Proliferation and Migration.International journal of molecular sciences · 2025Article
- Enhanced bypass of PD-L1 translation reduces the therapeutic response to mTOR kinase inhibitors.Cell reports · 2023Article
- Exploring the mTOR Signalling Pathway and Its Inhibitory Scope in Cancer.Pharmaceuticals (Basel, Switzerland) · 2023Review
- CDK13 phosphorylates the translation machinery and promotes tumorigenic protein synthesis.Oncogene · 2023Article
- Dual Target of EGFR and mTOR Suppresses Triple-Negative Breast Cancer Cell Growth by Regulating the Phosphorylation of mTOR Downstream Proteins.Breast cancer (Dove Medical Press) · 2023Article
- PI3K/AKT/mTOR signaling pathway activity in IDH-mutant diffuse glioma and clinical implications.Neuro-oncology · 2022Article
- An omic and multidimensional spatial atlas from serial biopsies of an evolving metastatic breast cancer.Cell reports. Medicine · 2022Article
- Interactions among mTORC, AMPK and SIRT: a computational model for cell energy balance and metabolism.Cell communication and signaling : CCS · 2021Article
- Reciprocal REGγ-mTORC1 regulation promotes glycolytic metabolism in hepatocellular carcinoma.Oncogene · 2021Article
- siRNA Knockdown of REDD1 Facilitates Aspirin-Mediated Dephosphorylation of mTORC1 Target 4E-BP1 in MDA-MB-468 Human Breast Cancer Cell Line.Cancer management and research · 2021Article
- Biomarkers and novel therapeutic approaches for diffuse large B-cell lymphoma in the era of precision medicine.Oncotarget · 2020Review
- Antagonists of the serotonin receptor 5A target human breast tumor initiating cells.BMC cancer · 2020Article
- The Synergistic Anti-Cancer Effects of NVP-BEZ235 and Regorafenib in Hepatocellular Carcinoma.Molecules (Basel, Switzerland) · 2020Article
- The Molecular Landscape and Biological Alterations Induced by PRAS40-Knockout in Head and Neck Squamous Cell Carcinoma.Frontiers in oncology · 2020Article
- Structure Determination, Functional Characterization, and Biosynthetic Implications of Nybomycin Metabolites from a Mining Reclamation Site-AssociatedJournal of natural products · 2019Article
- N-glycosylation-defective splice variants of neuropilin-1 promote metastasis by activating endosomal signals.Nature communications · 2019Article
- Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects.Cell chemical biology · 2019Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
The mTORC1 inhibitors, rapamycin and its analogs, are known to show only modest antitumor activity in clinic, but the underlying mechanisms remain largely elusive. Here, we found that activated AKT signaling is associated with rapamycin resistance in breast and colon cancers by sustained phosphorylation of the translational repressor 4E-BP1. Treatment of tumor cells with rapamycin or the AKT inhibitor MK2206 showed a limited activity in inhibiting 4E-BP1 phosphorylation, cap-dependent translation, cell growth and motility. However, treatment with both drugs resulted in profound effects in vitro and in vivo. Mechanistic investigation demonstrated that the combination treatment was required to effectively inhibit PRAS40 phosphorylation on both Ser183 and Thr246 mediated by mTORC1 and AKT respectively, and with the combined treatment, dephosphorylated PRAS40 binding to the raptor/mTOR complex was enhanced, leading to dramatic repression of mTORC1-regulated 4E-BP1 phosphorylation and translation. Knockdown of PRAS40 or 4E-BP1 expression markedly reduced the dependence of tumor cells on AKT/mTORC1 signaling for translation and survival. Together, these findings reveal a critical role of PRAS40 as an integrator of mTORC1 and AKT signaling for 4E-BP1-mediated translational regulation of tumor cell growth and motility, and highlight PRAS40 phosphorylation as a potential biomarker to evaluate the therapeutic response to mTOR/AKT inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.