RRC ID 74611
Author Muhowski EM, Ravikrishnan J, Gordon B, Yu L, Misra S, Walker B, Eathiraj S, Sampath D, Rogers KA, Byrd JC, Woyach JA.
Title Preclinical evaluation of combination nemtabrutinib and venetoclax in chronic lymphocytic leukemia.
Journal J Hematol Oncol
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.
Volume 15(1)
Pages 166
Published 2022-11-15
DOI 10.1186/s13045-022-01386-1
PII 10.1186/s13045-022-01386-1
PMID 36380319
PMC PMC9664697
MeSH Agammaglobulinaemia Tyrosine Kinase Animals Antineoplastic Agents* / pharmacology Antineoplastic Agents* / therapeutic use Leukemia, Lymphocytic, Chronic, B-Cell* / drug therapy Leukemia, Lymphocytic, Chronic, B-Cell* / pathology Lymphoma, B-Cell* / drug therapy Mice Protein Kinase Inhibitors / therapeutic use Proto-Oncogene Proteins c-bcl-2 Pyrazoles / therapeutic use Pyrimidines / pharmacology Pyrimidines / therapeutic use
IF 11.059
Human and Animal Cells StromaNKtert(RCB2350)