Journal article
Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication
Blood cancer journal (New York), Vol.11(2), pp.39-14
02/18/2021
DOI: 10.1038/s41408-021-00429-z
PMCID: PMC7893066
PMID: 33602908
Abstract
Ibrutinib inhibits Bruton tyrosine kinase while venetoclax is a specific inhibitor of the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL), and clinical trials using the combination therapy have produced remarkable results in terms of rate of complete remission and frequency of undetectable minimal residual disease. However, the laboratory rationale behind the success of the drug combination is still lacking. A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. Using an ex vivo model that promotes CLL proliferation, we show that modeled ibrutinib proliferative responses, but not viability responses, correlate well with patients' actual clinical responses. Importantly, we demonstrate for the first time that ibrutinib and venetoclax act on distinct CLL subpopulations that have different proliferative capacities. While the dividing subpopulation of CLL responds to ibrutinib, the resting subpopulation preferentially responds to venetoclax. The combination of these targeted therapies effectively reduced both the resting and dividing subpopulations in most cases. Our laboratory findings help explain several clinical observations and contribute to the understanding of tumor dynamics. Additionally, our proliferation model may be used to identify novel drug combinations with the potential of eradicating residual disease.
Details
- Title: Subtitle
- Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication
- Creators
- Pin Lu - Fox Chase Cancer CenterShengchun Wang - Fox Chase Cancer CenterCarrie A. Franzen - University of ChicagoGirish Venkataraman - University of ChicagoRebecca McClure - Health Sciences NorthLei Li - University of ChicagoWenjun Wu - Fox Chase Cancer CenterNifang Niu - University of ChicagoMadina Sukhanova - Northwestern UniversityJianming Pei - Fox Chase Cancer CenterDonald A. Baldwin - Fox Chase Cancer CenterReza Nejati - Fox Chase Cancer CenterMariusz A. Wasik - Fox Chase Cancer CenterNadia Khan - Fox Chase Cancer CenterYifan Tu - St Louis Univ, St Louis, MO 63103 USAJuehua Gao - Northwestern UniversityYihua Chen - Northwestern UniversityShuo Ma - Northwestern UniversityRichard A. Larson - University of ChicagoY. Lynn Wang - University of Chicago
- Resource Type
- Journal article
- Publication Details
- Blood cancer journal (New York), Vol.11(2), pp.39-14
- Publisher
- Springer Nature
- DOI
- 10.1038/s41408-021-00429-z
- PMID
- 33602908
- PMCID
- PMC7893066
- ISSN
- 2044-5385
- eISSN
- 2044-5385
- Number of pages
- 14
- Grant note
- Leukemia and Lymphoma Society TRP grant; Leukemia and Lymphoma Society
- Language
- English
- Date published
- 02/18/2021
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984701652002771
Metrics
11 Record Views