ArticleClinical cancer research : an official journal of the American Association for Cancer Research2011
Dual mTORC2/mTORC1 targeting results in potent suppressive effects on acute myeloid leukemia (AML) progenitors.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 96 citations in OpenAlex.
- Development of a SIN1 Targeting Inhibitor as a Novel Therapeutic Approach for the Treatment of Malignancies.Molecular cancer therapeutics · 2026Article
- Targeting the PI3K/AKT/mTOR signaling pathway in prostate cancer: Molecular dysregulation, therapeutic advances, and future directions.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2026Review
- PDCD4: A critical regulator in leukemic signaling networks and its therapeutic potential.Molecular biology reports · 2025Review
- Old drugs, new challenges: reassigning drugs for cancer therapies.Cellular & molecular biology letters · 2025Review
- Integrated systems biology analysis of acute lymphoblastic leukemia: unveiling molecular signatures and drug repurposing opportunities.Annals of hematology · 2024Article
- Targeting metabolism: A potential strategy for hematological cancer therapy.World journal of clinical cases · 2022Review
- Overcoming Drug Resistance in Advanced Prostate Cancer by Drug Repurposing.Medical sciences (Basel, Switzerland) · 2022Review
- Inhibitory effects of Tomivosertib in acute myeloid leukemia.Oncotarget · 2021Article
- Efficacy of a Novel Bi-Steric mTORC1 Inhibitor in Models of B-Cell Acute Lymphoblastic Leukemia.Frontiers in oncology · 2021Article
- Dual Kinase Targeting in Leukemia.Cancers · 2021Review
- Article
- Overcoming cancer therapeutic bottleneck by drug repurposing.Signal transduction and targeted therapy · 2020Review
- Targeting mTOR suppressed colon cancer growth through 4EBP1/eIF4E/PUMA pathway.Cancer gene therapy · 2020Article
- Sin1-mediated mTOR signaling in cell growth, metabolism and immune response.National science review · 2019Article
- Effects of Neddylation and mTOR Inhibition in Acute Myelogenous Leukemia.Translational oncology · 2019Article
- Article
- Signaling Pathways in Leukemic Stem Cells.Advances in experimental medicine and biology · 2019Review
- mTOR inhibition enhances efficacy of dasatinib inOncotarget · 2018Article
- The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia: a phase Ib/II study.Oncotarget · 2017Article
- Role of mTORC1-S6K1 signaling pathway in regulation of hematopoietic stem cell and acute myeloid leukemia.Experimental hematology · 2017Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
purposeTo determine whether mTORC2 and rapamycin-insensitive (RI)-mTORC1 complexes are present in acute myeloid leukemia (AML) cells and to examine the effects of dual mTORC2/mTORC1 inhibition on primitive AML leukemic progenitors. EXPERIMENTAL
designCombinations of different experimental approaches were used, including immunoblotting to detect phosphorylated/activated forms of elements of the mTOR pathway in leukemic cell lines and primary AML blasts; cell-proliferation assays; direct assessment of mRNA translation in polysomal fractions of leukemic cells; and clonogenic assays in methylcellulose to evaluate leukemic progenitor-colony formation.
resultsmTORC2 complexes are active in AML cells and play critical roles in leukemogenesis. RI-mTORC1 complexes are also formed and regulate the activity of the translational repressor 4E-BP1 in AML cells. OSI-027 blocks mTORC1 and mTORC2 activities and suppresses mRNA translation of cyclin D1 and other genes that mediate proliferative responses in AML cells. Moreover, OSI-027 acts as a potent suppressor of primitive leukemic precursors from AML patients and is much more effective than rapamycin in eliciting antileukemic effects in vitro.
conclusionsDual targeting of mTORC2 and mTORC1 results in potent suppressive effects on primitive leukemic progenitors from AML patients. Inhibition of the mTOR catalytic site with OSI-027 results in suppression of both mTORC2 and RI-mTORC1 complexes and elicits much more potent antileukemic responses than selective mTORC1 targeting with rapamycin.
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Registered trials
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