ArticleCancer chemotherapy and pharmacology2023
Resistance to the BCL-XL degrader DT2216 in T-cell acute lymphoblastic leukemia is rare and correlates with decreased BCL-XL proteolysis.
Article in Cancer chemotherapy and pharmacology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 16 citations in OpenAlex.
- Article
- Blocking Host Factors IAP and DDX3 Activates HIV-1 Transcription and Increases Apoptosis Sensitivity of HIV-1 Infected Cells.Pathogens (Basel, Switzerland) · 2026Article
- An Update on Clinically Advanced PROTAC Degraders and Their Synthesis.Molecules (Basel, Switzerland) · 2025Review
- Next-Generation Proteolysis-Targeting Chimeras in Precision Oncology: Multifunctional Designs, Emerging Modalities, and Translational Prospects in Targeted Protein Degradation.Drug development research · 2025Review
- Proteolysis-targeting chimeras in cancer therapy: Targeted protein degradation for next-generation treatment.Cancer · 2025Review
- Advancements in Proteolysis Targeting Chimeras for Targeted Therapeutic Strategies in Alzheimer's Disease.Molecular neurobiology · 2025Review
- Discovery of XZ338, a highly potent BCL-XEuropean journal of medicinal chemistry · 2025Article
- Advancements in PROTAC-based therapies for neurodegenerative diseases.Future medicinal chemistry · 2025Review
- Targeted protein degradation: advances in drug discovery and clinical practice.Signal transduction and targeted therapy · 2024Review
- PROteolysis-Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives.MedComm · 2024Review
- Anti-apoptotic protein BCL-XL as a therapeutic vulnerability in gastric cancer.Animal models and experimental medicine · 2023Article
- Review
- Protein degraders enter the clinic - a new approach to cancer therapy.Nature reviews. Clinical oncology · 2023Review
- BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival.Frontiers in oncology · 2023Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
purposeThe BCL-2 family of anti-apoptotic proteins, BCL-2, BCL-XL and MCL-1, can mediate survival of some types of cancer. DT2216 is a PROteolysis-TArgeting Chimera (PROTAC) that degrades BCL-XL specifically and is in phase 1 trials. We sought to define the frequency and mechanism of resistance to DT2216 in T-cell acute lymphoblastic leukemia (T-ALL) cell lines.
methodsWe measured cell survival and protein levels of BCL-XL, BCL-2, MCL-1 and the pro-apoptotic BIM in 13 distinct T-ALL cell lines after exposure to varying concentrations of DT2216.
resultsWe identified concentrations of DT2216 which were cytotoxic to each T-ALL cell line. These concentrations have no correlation with the initial protein levels of BCL-XL, BCL-2, MCL-1 or BIM in each cell line. However, there was a correlation between survival to DT2216 and the efficiency of degradation of BCL-XL by DT2216. Only one cell line, SUP-T1, had significant resistance to DT2216, defined as an IC50 above what is achievable in murine tumors in vivo.
conclusionResistance to DT2216 is rare in a wide variety of T-ALL cells but when it occurs is correlated with decreased BCL-XL degradation. Resistance to DT2216 in T-ALL is not predicted by initial BCL-XL or BIM protein levels, or BCL-2 or MCL-1 levels before or after treatment. These data imply that a phase 2 clinical trial of DT2216 in T-ALL should be widely available and not limited to a subset of patients.
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