Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
31004002
DOI
10.1158/1078-0432.ccr-18-3275
PII: 1078-0432.CCR-18-3275
Knihovny.cz E-resources
- MeSH
- Bridged Bicyclo Compounds, Heterocyclic pharmacology MeSH
- Drug Resistance, Neoplasm MeSH
- Humans MeSH
- Neoplasm Recurrence, Local drug therapy metabolism pathology MeSH
- Lymphoma, Mantle-Cell drug therapy metabolism pathology MeSH
- Mice, Inbred NOD MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors metabolism MeSH
- Antineoplastic Agents pharmacology MeSH
- Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors metabolism MeSH
- Pyrimidines pharmacology MeSH
- Sulfonamides pharmacology MeSH
- Drug Synergism * MeSH
- Thiophenes pharmacology MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- BCL2 protein, human MeSH Browser
- Bridged Bicyclo Compounds, Heterocyclic MeSH
- MCL1 protein, human MeSH Browser
- Myeloid Cell Leukemia Sequence 1 Protein MeSH
- Antineoplastic Agents MeSH
- Proto-Oncogene Proteins c-bcl-2 MeSH
- Pyrimidines MeSH
- S63845 MeSH Browser
- Sulfonamides MeSH
- Thiophenes MeSH
- venetoclax MeSH Browser
PURPOSE: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphomas characterized by (over)expression of BCL2. A BCL2-targeting drug, venetoclax, has promising anticancer activity in MCL. We analyzed molecular mechanisms of venetoclax resistance in MCL cells and tested strategies to overcome it. EXPERIMENTAL DESIGN: We confirmed key roles of proapoptotic proteins BIM and NOXA in mediating venetoclax-induced cell death in MCL. Both BIM and NOXA are, however, differentially expressed in cell lines compared with primary cells. First, NOXA protein is significantly overexpressed in most MCL cell lines. Second, deletions of BIM gene harbored by three commonly used MCL cell lines (JEKO-1, MINO, and Z138) were not found by array comparative genomic hybridization using a validation set of 24 primary MCL samples. RESULTS: We demonstrated that MCL1 and NOXA play important roles in mediating resistance to venetoclax. Consequently, we tested an experimental treatment strategy based on cotargeting BCL2 with venetoclax and MCL1 with a highly specific small-molecule MCL1 inhibitor S63845. The combination of venetoclax and S63845 demonstrated synthetic lethality in vivo on a panel of five patient-derived xenografts established from patients with relapsed MCL with adverse cytogenetics. CONCLUSIONS: Our data strongly support investigation of venetoclax in combination with S63845 as an innovative treatment strategy for chemoresistant MCL patients with adverse cytogenetics in the clinical grounds.
1st Medical Dept Charles University and General University Hospital Prague Czech Republic
Biocev 1st Faculty of Medicine Charles University Vestec Czech Republic
Biocev Institute of Biotechnology Czech Academy of Sciences Vestec Czech Republic
Faculty of Informatics and Statistics University of Economics Prague Czech Republic
Institute of Molecular Genetics Czech Academy of Sciences Prague Czech Republic
References provided by Crossref.org
Complex genetic and histopathological study of 15 patient-derived xenografts of aggressive lymphomas
BCL-2 Proteins in Pathogenesis and Therapy of B-Cell Non-Hodgkin Lymphomas
Drug Resistance in Non-Hodgkin Lymphomas
Advances in Molecular Biology and Targeted Therapy of Mantle Cell Lymphoma
