Faculty, Staff and Student Publications
Publication Date
11-15-2022
Journal
Journal of Hematology & Oncology
Abstract
Inhibitors of B cell receptor (BCR) signaling such as the Bruton's tyrosine kinase (BTK) inhibitors are effective therapeutics for chronic lymphocytic leukemia (CLL). The first-in-class covalent BTK inhibitor, ibrutinib, produces durable responses in most CLL patients; however, complete responses are only observed in a minority of patients. B cell lymphoma 2 (BCL2), an anti-apoptotic protein that contributes to CLL cell survival, has also been investigated as a therapeutic target. The BCL2 inhibitor venetoclax is effective in patients with CLL and can produce undetectable minimal residual disease, allowing discontinuation of therapy. In combination, ibrutinib and venetoclax have shown preclinical synergy and clinical efficacy. Nemtabrutinib is a next generation, reversible inhibitor of BTK that potently inhibits BCR signaling in treatment-naïve and ibrutinib-refractory CLL cells ex vivo. The clinical efficacy of combining BTK inhibitors with BCL2 inhibitors motivated us to evaluate the novel combination of nemtabrutinib and venetoclax. In vitro studies show that nemtabrutinib and venetoclax are not antagonistic to each other. In an adoptive transfer CLL mouse model, mice treated with nemtabrutinib and venetoclax had prolonged survival compared to mice treated with ibrutinib and venetoclax. Our preclinical studies further validate the combination of BTK inhibitors with venetoclax and justify further investigation of combining nemtabrutinib with venetoclax in CLL.
Keywords
Mice, Animals, Leukemia, Lymphocytic, Chronic, B-Cell, Agammaglobulinaemia Tyrosine Kinase, Pyrimidines, Pyrazoles, Lymphoma, B-Cell, Antineoplastic Agents, Proto-Oncogene Proteins c-bcl-2, Protein Kinase Inhibitors
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Hematology Commons, Hemic and Lymphatic Diseases Commons, Medical Sciences Commons, Neoplasms Commons, Oncology Commons
Comments
Supplementary Materials
Data Availability Statement
PMID: 36380319