Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell Lymphoma Article Swipe
Clare M. Adams
,
Amanda McBride
,
Peter Michener
,
Irina Shkundina
,
Ramkrishna Mitra
,
Hyun Hwan An
,
Pierluigi Porcu
,
Christine M. Eischen
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.3390/cancers16112130
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.3390/cancers16112130
Clinical trials with single-agent venetoclax/ABT-199 (anti-apoptotic BCL2 inhibitor) revealed that diffuse large B-cell lymphoma (DLBCL) is not solely dependent on BCL2 for survival. Gaining insight into pathways/proteins that increase venetoclax sensitivity or unique vulnerabilities in venetoclax-resistant DLBCL would provide new potential treatment avenues. Therefore, we generated acquired venetoclax-resistant DLBCL cells and evaluated these together with intrinsically venetoclax-resistant and -sensitive DLBCL lines. We identified resistance mechanisms, including alterations in BCL2 family members that differed between intrinsic and acquired venetoclax resistance and increased dependencies on specific pathways. Although combination treatments with BCL2 family member inhibitors may overcome venetoclax resistance, RNA-sequencing and drug/compound screens revealed that venetoclax-resistant DLBCL cells, including those with TP53 mutation, had a preferential dependency on oxidative phosphorylation. Mitochondrial electron transport chain complex I inhibition induced venetoclax-resistant, but not venetoclax-sensitive, DLBCL cell death. Inhibition of IDH2 (mitochondrial redox regulator) synergistically overcame venetoclax resistance. Additionally, both acquired and intrinsic venetoclax-resistant DLBCL cells were similarly sensitive to inhibitors of transcription, B-cell receptor signaling, and class I histone deacetylases. These approaches were also effective in DLBCL, follicular, and marginal zone lymphoma patient samples. Our results reveal there are multiple ways to circumvent or overcome the diverse venetoclax resistance mechanisms in DLBCL and other B-cell lymphomas and identify critical targetable pathways for future clinical investigations.
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- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.3390/cancers16112130
- https://www.mdpi.com/2072-6694/16/11/2130/pdf?version=1717421377
- OA Status
- gold
- Cited By
- 1
- References
- 84
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4399286909
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Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4399286909Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.3390/cancers16112130Digital Object Identifier
- Title
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Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell LymphomaWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2024Year of publication
- Publication date
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2024-06-03Full publication date if available
- Authors
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Clare M. Adams, Amanda McBride, Peter Michener, Irina Shkundina, Ramkrishna Mitra, Hyun Hwan An, Pierluigi Porcu, Christine M. EischenList of authors in order
- Landing page
-
https://doi.org/10.3390/cancers16112130Publisher landing page
- PDF URL
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https://www.mdpi.com/2072-6694/16/11/2130/pdf?version=1717421377Direct link to full text PDF
- Open access
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YesWhether a free full text is available
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goldOpen access status per OpenAlex
- OA URL
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https://www.mdpi.com/2072-6694/16/11/2130/pdf?version=1717421377Direct OA link when available
- Concepts
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Venetoclax, Cancer research, Lymphoma, Diffuse large B-cell lymphoma, Medicine, Biology, Leukemia, Chronic lymphocytic leukemia, ImmunologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
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1Total citation count in OpenAlex
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2025: 1Per-year citation counts (last 5 years)
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84Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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