Document Type
Article
Publication Date
6-3-2024
Abstract
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.
Recommended Citation
Adams, Clare M.; McBride, Amanda; Michener, Peter; Shkundina, Irina; Mitra, Ramkrishna; An, Hyun Hwan; Porcu, Pierluigi; and Eischen, Christine M., "Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell Lymphoma" (2024). Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers. Paper 19.
https://jdc.jefferson.edu/ppcbfp/19
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Language
English
Included in
Cancer Biology Commons, Chemical and Pharmacologic Phenomena Commons, Hemic and Lymphatic Diseases Commons, Neoplasms Commons
Comments
This article is the author's final published version in Cancers, Volume 16, Issue 11, June 2024, Article number 2130.
The published version is available at https://doi.org/10.3390/cancers16112130.
Copyright © 2024 by the authors