ArticleCell death & disease2024
Venetoclax triggers sublethal apoptotic signaling in venetoclax-resistant acute myeloid leukemia cells and induces vulnerability to PARP inhibition and azacitidine.
Article in Cell death & disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers, 1 of them a synthesis that pooled it.
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Who cites it
8 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Efficacy and safety of venetoclax plus azacitidine based regimens in the treatment of relapsed or refractory acute myeloid leukemia: a systematic review and meta-analysis.Annals of hematology · 2025Pooled it
- Evasion of cell death despite mitochondrial outer membrane permeabilization: an oncogenic outcome of apoptosis.Apoptosis : an international journal on programmed cell death · 2026Review
- CHRNB4-Mediated Neuroactive Signaling Rewiring Drives Adaptive Resistance to BCL-2 Inhibition in Acute Myeloid Leukemia.Cancers · 2026Article
- Predictors of response and rational combinations for the novel MCL-1 inhibitor MIK665 in acute myeloid leukemia.Molecular oncology · 2026Article
- Rewired Neuroactive Ligand-Receptor Signaling Confers Adaptive Resistance to BCL-2 Inhibition in AML.Research square · 2026Article
- Article
- Augmenting the Anti-Leukemic Activity of the BCL-2 Inhibitor Venetoclax Through Its Transformation Into Polypharmacologic Dual BCL-2/HDAC1 and Dual BCL-2/HDAC6 Inhibitors.Drug development research · 2025Article
- Bax- Bcl-xL interaction dynamics during the progression of cell cycle and cell death using FLIM-FRET.Cell stress · 2025Review
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Authors and funding
9 authors.
Funding
Abstract
Venetoclax plus azacitidine treatment is clinically beneficial for elderly and unfit acute myeloid leukemia (AML) patients. However, the treatment is rarely curative, and relapse due to resistant disease eventually emerges. Since no current clinically feasible treatments are known to be effective at the state of acquired venetoclax resistance, this is becoming a major challenge in AML treatment. Studying venetoclax-resistant AML cell lines, we observed that venetoclax induced sublethal apoptotic signaling and DNA damage even though cell survival and growth were unaffected. This effect could be due to venetoclax inducing a sublethal degree of mitochondrial outer membrane permeabilization. Based on these results, we hypothesized that the sublethal apoptotic signaling induced by venetoclax could constitute a vulnerability in venetoclax-resistant AML cells. This was supported by screens with a broad collection of drugs, where we observed a synergistic effect between venetoclax and PARP inhibition in venetoclax-resistant cells. Additionally, the venetoclax-PARP inhibitor combination prevented the acquisition of venetoclax resistance in treatment naïve AML cell lines. Furthermore, the addition of azacitidine to the venetoclax-PARP inhibitor combination enhanced venetoclax induced DNA damage and exhibited exceptional sensitivity and long-term responses in the venetoclax-resistant AML cell lines and samples from AML patients that had clinically relapsed under venetoclax-azacitidine therapy. In conclusion, we mechanistically identify a new vulnerability in acquired venetoclax-resistant AML cells and identify PARP inhibition as a potential therapeutic approach to overcome acquired venetoclax resistance in AML.
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