ArticleClinical cancer research : an official journal of the American Association for Cancer Research2014
Antagonism of SET using OP449 enhances the efficacy of tyrosine kinase inhibitors and overcomes drug resistance in myeloid leukemia.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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Who cites it
79 citing papers in PubMed, 124 citations in OpenAlex.
- SET alpha and SET beta mRNA isoforms in chronic lymphocytic leukaemia.British journal of haematology · 2019Trial
- Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors.Leukemia · 2026Article
- Recent Advances in FLT3-Based Dual Inhibitors: A Promising Strategy for the Treatment of Acute Myeloid Leukemia.Current medicinal chemistry · 2026Review
- Targeting SET to counteract Lyn activation demonstrates anti-cancer potential in diffuse large B-cell lymphoma.Clinical and experimental medicine · 2025Article
- Protein Phosphatase 2A Promotes CD8Research (Washington, D.C.) · 2025Article
- Novel targeted therapies in chronic myeloid leukemia.Pharmaceutical science advances · 2024Review
- The next decade of SET: from an oncoprotein to beyond.Journal of molecular cell biology · 2024Review
- Altering phosphorylation in cancer through PP2A modifiers.Cancer cell international · 2024Review
- Pharmacological Effects of FTY720 and its Derivatives.Current topics in medicinal chemistry · 2024Review
- Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases.Medicina (Kaunas, Lithuania) · 2023Review
- Circular MTHFD2L RNA-encoded CM-248aa inhibits gastric cancer progression by targeting the SET-PP2A interaction.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Promising Molecular Targets in Pharmacological Therapy for Neuronal Damage in Brain Injury.Antioxidants (Basel, Switzerland) · 2023Review
- Thirty years of SET/TAF1β/I2PP2A: from the identification of the biological functions to its implications in cancer and Alzheimer's disease.Bioscience reports · 2022Review
- Review
- The E3 Ligase TRIM4 Facilitates SET Ubiquitin-Mediated Degradation to Enhance ER-α Action in Breast Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A.iScience · 2022Article
- T-cell Dysfunction upon Expression of MYC with Altered Phosphorylation at Threonine 58 and Serine 62.Molecular cancer research : MCR · 2022Article
- Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy.Signal transduction and targeted therapy · 2022Review
- PPP2CA Is a Novel Therapeutic Target in Neuroblastoma Cells That Can Be Activated by the SET Inhibitor OP449.Frontiers in oncology · 2022Article
- Chronic myeloid leukemia stem cells: targeting therapeutic implications.Stem cell research & therapy · 2021Review
19 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
purposeThe SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A), is overexpressed in leukemia. We evaluated the efficacy of SET antagonism in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) cell lines, a murine leukemia model, and primary patient samples using OP449, a specific, cell-penetrating peptide that antagonizes SET's inhibition of PP2A. EXPERIMENTAL
designIn vitro cytotoxicity and specificity of OP449 in CML and AML cell lines and primary samples were measured using proliferation, apoptosis, and clonogenic assays. Efficacy of target inhibition by OP449 was evaluated by immunoblotting and PP2A assay. In vivo antitumor efficacy of OP449 was measured in human HL-60 xenografted murine model.
resultsWe observed that OP449 inhibited growth of CML cells including those from patients with blastic phase disease and patients harboring highly drug-resistant BCR-ABL1 mutations. Combined treatment with OP449 and ABL1 tyrosine kinase inhibitors was significantly more cytotoxic to K562 cells and primary CD34(+) CML cells. SET protein levels remained unchanged with OP449 treatment, but BCR-ABL1-mediated downstream signaling was significantly inhibited with the degradation of key signaling molecules such as BCR-ABL1, STAT5, and AKT. Similarly, AML cell lines and primary patient samples with various genetic lesions showed inhibition of cell growth after treatment with OP449 alone or in combination with respective kinase inhibitors. Finally, OP449 reduced the tumor burden of mice xenografted with human leukemia cells.
conclusionsWe demonstrate a novel therapeutic paradigm of SET antagonism using OP449 in combination with tyrosine kinase inhibitors for the treatment of CML and AML.
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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.