ArticleOncogene2018
The BET bromodomain inhibitor CPI203 overcomes resistance to ABT-199 (venetoclax) by downregulation of BFL-1/A1 in in vitro and in vivo models of MYC+/BCL2+ double hit lymphoma.
Article in Oncogene, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 1 of them a synthesis that pooled it.
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Who cites it
54 citing papers in PubMed, 1 synthesis or guideline pooled it, 81 citations in OpenAlex.
- Using Informatics Tools to Identify Opportunities for Precision Medicine in Diffuse Large B-cell Lymphoma.Clinical lymphoma, myeloma & leukemia · 2020Pooled it
- Anti-apoptotic BCL-2 family proteins: from regulatory networks to therapeutic targeting.Oncogenesis · 2026Review
- Curcumin induces and enhances the PARP1-mediated parthanatos in diffuse large B cell lymphoma.Oncology letters · 2026Article
- The EP300-Targeting Drug CCS1477 Inhibits the Growth and Development of Diffuse Large B-Cell Lymphoma by Promoting Apoptosis and Mitophagy to Reduce Drug Resistance.Anti-cancer agents in medicinal chemistry · 2026Article
- Potential therapeutic GSK-3β inhibitor 9-ING-41 is active in combination with venetoclax in double-hit lymphoma (DHL).Cancer biology & therapy · 2025Article
- BET inhibition revealed varying MYC dependency mechanisms independent of gene alterations in aggressive B-cell lymphomas.Clinical epigenetics · 2024Article
- Bromodomain proteins as potential therapeutic targets for B-cell non-Hodgkin lymphoma.Cell & bioscience · 2024Review
- Inhibition of bromodomain and extra-terminal proteins targets constitutively active NFκB and STAT signaling in lymphoma and influences the expression of the antiapoptotic proteins BCL2A1 and c-MYC.Cell communication and signaling : CCS · 2024Article
- Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell Lymphoma.Cancers · 2024Article
- Mediator kinase inhibition impedes transcriptional plasticity and prevents resistance to ERK/MAPK-targeted therapy in KRAS-mutant cancers.NPJ precision oncology · 2024Article
- Bromodomain and extraterminal (BET) proteins: biological functions, diseases, and targeted therapy.Signal transduction and targeted therapy · 2023Review
- Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers.Research square · 2023Article
- Targeting MYC-driven lymphoma: lessons learned and future directions.Cancer drug resistance (Alhambra, Calif.) · 2023Review
- Drug-Resistance Mechanism and New Targeted Drugs and Treatments of Relapse and Refractory DLBCL.Cancer management and research · 2023Review
- Therapeutic efficacy of an injectable formulation of purinostat mesylate in SU-DHL-6 tumour model.Annals of medicine · 2022Article
- Last but not least: BFL-1 as an emerging target for anti-cancer therapies.Biochemical Society transactions · 2022Review
- Maximal Activation of Apoptosis Signaling by Cotargeting Antiapoptotic Proteins in BH3 Mimetic-Resistant AML and AML Stem Cells.Molecular cancer therapeutics · 2022Article
- Altered pathways and targeted therapy in double hit lymphoma.Journal of hematology & oncology · 2022Review
- BCL2A1 regulates Canady Helios Cold Plasma-induced cell death in triple-negative breast cancer.Scientific reports · 2022Article
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Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, mostly known as double-hit lymphoma (DHL), is a rare entity characterized by morphologic and molecular features between Burkitt lymphoma and the clinically manageable diffuse large B-cell lymphoma (DLBCL). DHL patients usually undergo a rapidly progressing clinical course associated with resistance to standard chemo-immunotherapy. As a consequence, the prognosis of this entity is particularly poor with a median overall survival inferior to 1 year. ABT-199 (venetoclax) is a potent and selective small-molecule antagonist of BCL-2 recently approved for the treatment of a specific subtype of lymphoid neoplasm. In this study, we demonstrate that single-agent ABT-199 efficiently displaces BAX from BCL-2 complexes but fails to maintain a significant antitumor activity over time in most MYC+/BCL2+DHL cell lines and primary cultures, as well as in a xenograft mouse model of the disease. We further identify the accumulation of the BCL2-like protein BFL-1 to be a major mechanism involved in acquired resistance to ABT-199. Noteworthy, this phenomenon can be counteracted by the BET bromodomain inhibitor CPI203, since gene expression profiling identifies BCL2A1, the BFL-1 coding gene, as one of the top apoptosis-related gene modulated by this compound. Upon CPI203 treatment, simultaneous downregulation of MYC and BFL-1 further overcomes resistance to ABT-199 both in vitro and in vivo, engaging synergistic caspase-mediated apoptosis in DHL cultures and tumor xenografts. Together, these findings highlight the relevance of BFL-1 in DH lymphoma-associated drug resistance and support the combined use of a BCL-2 antagonist and a BET inhibitor as a promising therapeutic strategy for patients with aggressive DHL.
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