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Lu P , Wang S , Franzen CA , Venkataraman G , McClure R , Li L , Wu W , Niu N , Sukhanova M , Pei J , Baldwin DA , Nejati R , Wasik MA , Khan N , Tu Y , Gao J , Chen Y , Ma S , Larson RA , Wang YL
Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication
Blood Cancer J. 2021 Feb 18;11(2) :39
PMID: 33602908    PMCID: PMC7893066    URL: https://www.ncbi.nlm.nih.gov/pubmed/33602908
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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.
Notes
2044-5385 Lu, Pin Wang, Shengchun Orcid: 0000-0003-2296-1577 Franzen, Carrie A Venkataraman, Girish McClure, Rebecca Li, Lei Wu, Wenjun Niu, Nifang Sukhanova, Madina Orcid: 0000-0002-1843-7038 Pei, Jianming Baldwin, Donald A Nejati, Reza Wasik, Mariusz A Khan, Nadia Tu, Yifan Gao, Juehua Chen, Yihua Ma, Shuo Larson, Richard A Orcid: 0000-0001-9168-3203 Wang, Y Lynn Orcid: 0000-0003-0773-1212 Journal Article United States Blood Cancer J. 2021 Feb 18;11(2):39. doi: 10.1038/s41408-021-00429-z.