RRC ID 56923
Author Deng J, Isik E, Fernandes SM, Brown JR, Letai A, Davids MS.
Title Bruton's tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia.
Journal Leukemia
Abstract Although the BTK inhibitor ibrutinib has transformed the management of patients with chronic lymphocytic leukemia (CLL), it does not induce substantial apoptosis in vitro, and as such the mechanisms underlying its ability to kill CLL cells are not well understood. Acalabrutinib, a more specific BTK inhibitor now in development, also appears to be highly effective in CLL, but the connection of its mechanism with CLL cell death is also unclear. Using dynamic BH3 profiling, we analyzed alterations in the function of the mitochondrial apoptotic pathway induced by ibrutinib and acalabrutinib. We studied CLL patient samples treated ex vivo with both drugs, as well as primary samples from CLL patients on clinical trials of both drugs. We found that BTK inhibition enhances mitochondrial BCL-2 dependence without significantly altering overall mitochondrial priming. Enhancement of BCL-2 dependence was accompanied by an increase in the pro-apoptotic protein BIM. In contrast, treatment with the selective BCL-2 inhibitor venetoclax enhanced overall mitochondrial priming without increasing BCL-2 dependence. Pre-treatment of CLL cells with either BTK inhibitor, whether ex vivo or in vivo in patients, enhanced killing by venetoclax. Our data suggest that BTK inhibition enhances mitochondrial BCL-2 dependence, supporting the ongoing development of clinical trials combining BTK and BCL-2 inhibition.
Volume 31(10)
Pages 2075-2084
Published 2017-10-1
DOI 10.1038/leu.2017.32
PII leu201732
PMID 28111464
PMC PMC5555835
MeSH Adenine / analogs & derivatives Agammaglobulinaemia Tyrosine Kinase Antineoplastic Combined Chemotherapy Protocols / therapeutic use* Apoptosis / drug effects Bcl-2-Like Protein 11 / biosynthesis Bcl-2-Like Protein 11 / genetics Benzamides / administration & dosage Benzamides / pharmacology* Benzamides / therapeutic use Bridged Bicyclo Compounds, Heterocyclic / administration & dosage Bridged Bicyclo Compounds, Heterocyclic / agonists* Bridged Bicyclo Compounds, Heterocyclic / pharmacology Bridged Bicyclo Compounds, Heterocyclic / therapeutic use Clinical Trials as Topic Drug Resistance, Neoplasm / drug effects* Drug Screening Assays, Antitumor Drug Synergism Humans Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy* Leukemia, Lymphocytic, Chronic, B-Cell / pathology Mitochondria / drug effects Molecular Targeted Therapy* Neoplasm Proteins / antagonists & inhibitors* Neoplasm Proteins / physiology Peptide Fragments Piperidines Protein Kinase Inhibitors / administration & dosage Protein Kinase Inhibitors / pharmacology* Protein Kinase Inhibitors / therapeutic use Protein-Tyrosine Kinases / antagonists & inhibitors* Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 / physiology* Pyrazines / administration & dosage Pyrazines / pharmacology* Pyrazines / therapeutic use Pyrazoles / administration & dosage Pyrazoles / pharmacology* Pyrazoles / therapeutic use Pyrimidines / administration & dosage Pyrimidines / pharmacology* Pyrimidines / therapeutic use Sulfonamides / administration & dosage Sulfonamides / agonists* Sulfonamides / pharmacology Sulfonamides / therapeutic use
IF 9.944
Times Cited 53
Human and Animal Cells StromaNKtert(RCB2350)