ArticleCancer research2010
Essential requirement for PP2A inhibition by the oncogenic receptor c-KIT suggests PP2A reactivation as a strategy to treat c-KIT+ cancers.
Article in Cancer research, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers, 1 of them a synthesis that pooled it.
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Who cites it
63 citing papers in PubMed, 1 synthesis or guideline pooled it, 130 citations in OpenAlex.
- A systematic evaluation of the safety and toxicity of fingolimod for its potential use in the treatment of acute myeloid leukaemia.Anti-cancer drugs · 2016Pooled it
- Identifying key genes and functionally enriched pathways in acute myeloid leukemia by weighted gene co-expression network analysis.Journal of applied genetics · 2025Article
- Protein Phosphatase 2A Promotes CD8Research (Washington, D.C.) · 2025Article
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- Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders.Nature reviews. Drug discovery · 2023Review
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- A genome-scale CRISPR Cas9 dropout screen identifies synthetically lethal targets in SRC-3 inhibited cancer cells.Communications biology · 2021Article
- PP2A and Its Inhibitors in Helper T-Cell Differentiation and Autoimmunity.Frontiers in immunology · 2021Review
- Repression of sphingosine kinase (SK)-interacting protein (SKIP) in acute myeloid leukemia diminishes SK activity and its re-expression restores SK function.The Journal of biological chemistry · 2020Article
- Review
- The role of exosomes and MYC in therapy resistance of acute myeloid leukemia: Challenges and opportunities.Molecular aspects of medicine · 2019Review
- The Role of Reactive Oxygen Species in Acute Myeloid Leukaemia.International journal of molecular sciences · 2019Review
- FTY720 induces non-canonical phosphatidylserine externalization and cell death in acute myeloid leukemia.Cell death & disease · 2019Article
- Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration.Pharmacology & therapeutics · 2019Review
- Penfluridol triggers cytoprotective autophagy and cellular apoptosis through ROS induction and activation of the PP2A-modulated MAPK pathway in acute myeloid leukemia with different FLT3 statuses.Journal of biomedical science · 2019Article
- The NMR-based characterization of the FTY720-SET complex reveals an alternative mechanism for the attenuation of the inhibitory SET-PP2A interaction.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- Review
- Multiple Sclerosis and Cancer: The Ying-Yang Effect of Disease Modifying Therapies.Frontiers in immunology · 2019Review
- BCR-ABL Independent Mechanisms of Resistance in Chronic Myeloid Leukemia.Frontiers in oncology · 2019Review
3 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
Oncogenic mutations of the receptor tyrosine kinase c-KIT play an important role in the pathogenesis of gastrointestinal stromal tumors, systemic mastocytosis, and some acute myeloid leukemias (AML). Although juxtamembrane mutations commonly detected in gastrointestinal stromal tumor are sensitive to tyrosine kinase inhibitors, the kinase domain mutations frequently encountered in systemic mastocytosis and AML confer resistance and are largely unresponsive to targeted inhibition by the existing agent imatinib. In this study, we show that myeloid cells expressing activated c-KIT mutants that are imatinib sensitive (V560G) or imatinib resistant (D816V) can inhibit the tumor suppressor activity of protein phosphatase 2A (PP2A). This effect was associated with the reduced expression of PP2A structural (A) and regulatory subunits (B55alpha, B56alpha, B56gamma, and B56delta). Overexpression of PP2A-Aalpha in D816V c-KIT cells induced apoptosis and inhibited proliferation. In addition, pharmacologic activation of PP2A by FTY720 reduced proliferation, inhibited clonogenic potential, and induced apoptosis of mutant c-KIT(+) cells, while having no effect on wild-type c-KIT cells or empty vector controls. FTY720 treatment caused the dephosphorylation of the D816V c-KIT receptor and its downstream signaling targets pAkt, pSTAT5, and pERK1/2. Additionally, in vivo administration of FTY720 delayed the growth of V560G and D816V c-KIT tumors, inhibited splenic and bone marrow infiltration, and prolonged survival. Our findings show that PP2A inhibition is essential for c-KIT-mediated tumorigenesis, and that reactivating PP2A may offer an attractive strategy to treat drug-resistant c-KIT(+) cancers.
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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.