ArticleJournal of hematology & oncology2018
A loss-of-function genetic screening reveals synergistic targeting of AKT/mTOR and WTN/β-catenin pathways for treatment of AML with high PRL-3 phosphatase.
Article in Journal of hematology & oncology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 39 citations in OpenAlex.
- Safety Assessment of Extracellular Vesicle-Based Therapy in Regenerative Dentistry.International journal of molecular sciences · 2026Review
- PRL-3 as a metastasis-associated phosphatase in colorectal cancer: Mechanisms and therapeutic strategies.Clinical & experimental metastasis · 2025Review
- WNT signaling in cancer: molecular mechanisms and potential therapies.Molecular biomedicine · 2025Review
- PRL-3: unveiling a new horizon in cancer therapy.Acta pharmacologica Sinica · 2025Review
- Targeting Wnt Signaling in Acute Lymphoblastic Leukemia.Cancers · 2025Review
- The joint role of the immune microenvironment and NFrontiers in genetics · 2025Article
- RHOF activation of AKT/β-catenin signaling pathway drives acute myeloid leukemia progression and chemotherapy resistance.iScience · 2024Article
- Protein Tyrosine Phosphatase PRL-3: A Key Player in Cancer Signaling.Biomolecules · 2024Review
- Curcumin and its Derivatives Targeting Multiple Signaling Pathways to Elicit Anticancer Activity: A Comprehensive Perspective.Current medicinal chemistry · 2024Review
- Super-enhancer-driven TOX2 mediates oncogenesis in Natural Killer/T Cell Lymphoma.Molecular cancer · 2023Article
- Wnt/β-Catenin Signaling Pathway in the Development and Progression of Colorectal Cancer.Cancer management and research · 2023Review
- PRL3 as a therapeutic target for novel cancer immunotherapy in multiple cancer types.Theranostics · 2023Review
- Bone Marrow Microenvironment as a Source of New Drug Targets for the Treatment of Acute Myeloid Leukaemia.International journal of molecular sciences · 2022Review
- FOXO3a‑modulated DEPDC1 promotes malignant progression of nephroblastoma via the Wnt/β‑catenin signaling pathway.Molecular medicine reports · 2022Article
- Targeting β-catenin in acute myeloid leukaemia: past, present, and future perspectives.Bioscience reports · 2022Review
- CystathionineOxidative medicine and cellular longevity · 2022Article
- CrossTORC and WNTegration in Disease: Focus on Lymphangioleiomyomatosis.International journal of molecular sciences · 2021Review
- Targeting the Wnt/β-catenin signaling pathway in cancer.Journal of hematology & oncology · 2020Review
- Wnt Signaling in Leukemia and Its Bone Marrow Microenvironment.International journal of molecular sciences · 2020Review
- Therapeutic Target Discovery Using High-Throughput Genetic Screens in Acute Myeloid Leukemia.Cells · 2020Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundProtein tyrosine phosphatase of regenerating liver 3 (PRL-3) is overexpressed in a subset of AML patients with inferior prognosis, representing an attractive therapeutic target. However, due to relatively shallow pocket of the catalytic site of PRL-3, it is difficult to develop selective small molecule inhibitor.
methodsIn this study, we performed whole-genome lentiviral shRNA library screening to discover synthetic lethal target to PRL-3 in AML. We used specific small molecule inhibitors to validate the synthetic lethality in human PRL-3 high vs PRL-3 low human AML cell lines and primary bone marrow cells from AML patients. AML mouse xenograft model was used to examine the in vivo synergism.
resultsThe list of genes depleted in TF1-hPRL3 cells was particularly enriched for members involved in WNT/β-catenin pathway and AKT/mTOR signaling. These findings prompted us to explore the impact of AKT/mTOR signaling inhibition in PRL-3 high AML cells in combination with WNT/β-catenin inhibitor. VS-5584, a novel, highly selective dual PI3K/mTOR inhibitor, and ICG-001, a WNT inhibitor, were used as a combination therapy. A synthetic lethal interaction between mTOR/AKT pathway inhibition and WNT/β-catenin was validated by a variety of cellular assays. Notably, we found that treatment with these two drugs significantly reduced leukemic burden and prolonged survival of mice transplanted with human PRL-3 high AML cells, but not with PRL-3 low AML cells.
conclusionsIn summary, our results support the existence of cooperative signaling networks between AKT/mTOR and WNT/β-catenin pathways in PRL-3 high AML cells. Simultaneous inhibition of these two pathways could achieve robust clinical efficacy for this subtype of AML patient with high PRL-3 expression and warrant further clinical investigation.
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