ArticleBlood2022
Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia.
Article in Blood, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 43 citations in OpenAlex.
- Not only a therapeutic target; mTOR in Hodgkin lymphoma and acute lymphoblastic leukemia.Frontiers in oncology · 2024Pooled it
- Genomic Subtype Influences BH3 Mimetic Drug Sensitivity and Synergy with Cytotoxic Chemotherapeutics in T-cell Acute Lymphoblastic Leukemia.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Temsirolimus safety evaluation: real-world adverse event analysis from the FDA adverse event reporting system database.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Mechanistic role of GNE-987 targeting BRD4-HCP5 axis in pediatric T-cell acute lymphoblastic leukemia.Journal of cell communication and signaling · 2026Article
- ELDA: real-time functional drug profiling in acute lymphoblastic leukemia.Frontiers in oncology · 2026Article
- Review
- Relapsed childhood T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma.Haematologica · 2025Review
- Development of a cuproptosis-related prognostic signature to reveal heterogeneity of the immune microenvironment and drug sensitivity in acute lymphoblastic leukemia.European journal of medical research · 2025Article
- Post-Translational Modifications in Multiple Myeloma: Mechanisms of Drug Resistance and Therapeutic Opportunities.Biomolecules · 2025Review
- UNC119 regulates T-cell receptor signalling in primary T cells and T acute lymphocytic leukaemia.Life science alliance · 2025Article
- MultiplexedbioRxiv : the preprint server for biology · 2025Article
- Advances in the combination of CAR-T therapy with small-molecule reagents for hematologic malignancies.Frontiers in immunology · 2025Review
- Advances in the application of patient-derived xenograft models in acute leukemia resistance.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Targeted therapy for leukemia based on nanomaterials.Heliyon · 2024Review
- Therapeutic Strategies for Angiogenesis Based on Endothelial Cell Epigenetics.Journal of cardiovascular translational research · 2024Review
- Rapamycin increases leukemia cell sensitivity to chemotherapy by regulating mTORC1 pathway-mediated apoptosis and autophagy.International journal of hematology · 2024Article
- Unlocking the potential of T-cell metabolism reprogramming: Advancing single-cell approaches for precision immunotherapy in tumour immunity.Clinical and translational medicine · 2024Review
- Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing.Nature communications · 2024Article
- Pathway of LCK Tyrosine Kinase and mTOR Signaling in Children with T-Cell Acute Lymphoblastic Leukemia.The application of clinical genetics · 2024Review
- Advancements in the impact of human microbiota and probiotics on leukemia.Frontiers in microbiology · 2024Review
Corrections and comments
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Authors and funding
27 authors at 8 institutions in 3 countries.
Funding
Abstract
Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 (mammalian target of rapamycin complex 1) inhibitors and the general tyrosine kinase inhibitor dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts (PDX) grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway, and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs.
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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.