ArticleClinical cancer research : an official journal of the American Association for Cancer Research2019
NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers, 1 of them a synthesis that pooled it.
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Who cites it
14 citing papers in PubMed, 1 synthesis or guideline pooled it, 17 citations in OpenAlex.
- Nelarabine in T-cell acute lymphoblastic leukemia: intracellular metabolism and molecular mode-of-action.Leukemia · 2025Pooled it
- Evaluation of Darifenacin for T-Cell Acute Lymphoblastic Leukemia: Selective Targeting of the Non-Neuronal Cholinergic System and Lysosomal Cathepsins.International journal of molecular sciences · 2026Article
- Targeting Bcl-2 with Indole Scaffolds: Emerging Drug Design Strategies for Cancer Treatment.Mini reviews in medicinal chemistry · 2025Review
- Notch Inhibitors and BH3 Mimetics in T-Cell Acute Lymphoblastic Leukemia.International journal of molecular sciences · 2024Review
- Adenoid cystic carcinoma: insights from molecular characterization and therapeutic advances.MedComm · 2024Review
- Effective Targeting of Melanoma Cells by Combination of Mcl-1 and Bcl-2/Bcl-xInternational journal of molecular sciences · 2024Article
- Synergistic activity of ABT-263 and ONC201/TIC10 against solid tumor cell lines is associated with suppression of anti-apoptotic Mcl-1, BAG3, pAkt, and upregulation of pro-apoptotic Noxa and Bax cleavage during apoptosis.American journal of cancer research · 2023Article
- Notch-Signaling Deregulation Induces Myeloid-Derived Suppressor Cells in T-Cell Acute Lymphoblastic Leukemia.Frontiers in immunology · 2022Article
- Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures.Nature communications · 2021Article
- T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies.Blood cancer discovery · 2021Review
- Review
- Strategies to Overcome Resistance Mechanisms in T-Cell Acute Lymphoblastic Leukemia.International journal of molecular sciences · 2019Review
- The Key Roles of PTEN in T-Cell Acute Lymphoblastic Leukemia Development, Progression, and Therapeutic Response.Cancers · 2019Review
- Targeting mTOR in Acute Lymphoblastic Leukemia.Cells · 2019Review
Corrections and comments
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Authors and funding
19 authors at 5 institutions in 2 countries.
Funding
Abstract
purposeEffective targeted therapies are lacking for refractory and relapsed T-cell acute lymphoblastic leukemia (T-ALL). Suppression of the NOTCH pathway using gamma-secretase inhibitors (GSI) is toxic and clinically not effective. The goal of this study was to identify alternative therapeutic strategies for T-ALL. EXPERIMENTAL
designWe performed a comprehensive analysis of our high-throughput drug screen across hundreds of human cell lines including 15 T-ALL models. We validated and further studied the top hit, navitoclax (ABT-263). We used multiple human T-ALL cell lines as well as primary patient samples, and performed both
resultsWe found that T-ALL are hypersensitive to navitoclax, an inhibitor of BCL2 family of antiapoptotic proteins. Importantly, GSI-resistant T-ALL are also susceptible to navitoclax. Sensitivity to navitoclax is due to low levels of MCL-1 in T-ALL. We identify an unsuspected regulation of mTORC1 by the NOTCH pathway, resulting in increased MCL-1 upon GSI treatment. Finally, we show that pharmacologic inhibition of mTORC1 lowers MCL-1 levels and further sensitizes cells to navitoclax
conclusionsOur results support the development of navitoclax, as single agent and in combination with mTOR inhibitors, as a new therapeutic strategy for T-ALL, including in the setting of GSI resistance.
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Registered trials
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