Mechanistic Insight on Antiapoptotic Multidrug-Resistant Phenotype of CLL
Posted: Tuesday, November 9, 2021
A study performed by Timothy P. Bender, PhD, of the University of Virginia School of Medicine, Charlottesville, and colleagues analyzed the expression of antiapoptotic proteins in CLL cells in vivo and determined their responsiveness to BCL2 homology (BH)-domain antagonists. These investigators discovered that activated CLL B cells that emigrated from the lymph nodes overexpress antiapoptotic proteins, potentially influencing resistance to therapies such as the BCL2 inhibitor venetoclax. Published in the journal Blood Advances, their findings shed light on the mechanisms behind activation marker expression as well as clinical outcomes.
Whole blood was collected from treated and treatment-naive patients with CLL, and peripheral blood mononuclear cells were analyzed via flow cytometry. An assortment of drugs was used to analyze responsiveness: ibrutinib, bendamustine, fludarabine, and venetoclax.
Significant overexpression of the antiapoptotic protein Bcl-2 was observed in CLL cells when compared with normal CD5-positive lymphocytes. Other proteins, such as Mcl-1 and Bcl-xl, also demonstrated a trend toward elevated expression in both treated and treatment-naive individuals. Additionally, the proapoptotic protein Bim appeared to show upregulated or unaltered expression in CLL cells. Of note, these cells also exhibited antiapoptotic resistance to BH-domain antagonists when tested as single agents, suggesting that overexpression may be the likely generator of resistance.
When using venetoclax as an anchor drug, combinations including inhibitors of NF-κB signaling subnetworks that also inhibit NEDD8-activating enzyme (pevonedistat/MLN4924), proteasome (bortezomib), or MALT1 (MI-2), appeared to be effective in conquering multidrug-resistance. Although these agents induced selective apoptosis in CLL cells when combined, it led to significant toxicity of normal cells. Similar screening with the MCL1 inhibitor S63845 as an anchor drug was also effective in overcoming resistance, but these therapies exhibited limited selectivity for leukemic B cells.
Disclosure: For full disclosures of the study authors, visit ashpublications.org.