Expression Profile of BCL-2, BCL-X L , and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models
| Autor: | Ellen Ingalla, Elizabeth Punnoose, Sophie Maïga, Franklin Peale, Deepak Sampath, Lisa D. Belmont, Wayne J. Fairbrother, Erwin R. Boghaert, Amy Young, Paul Tapang, Nguyen Tan, Walter C. Darbonne, Leslie Lee, Anatol Oleksijew, Joel D. Leverson, Michael J. Mitten, Jason Oeh, Martine Amiot, Peng Yue, Andrew J. Souers |
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| Přispěvatelé: | Oncology Biomarkers, Genentech, Inc. [San Francisco], Oncology Development, Abbvie Inc. [North Chicago], Research Pathology, Oncology Discovery, Abbvie Inc.: North Chicago, Discovery Oncology, Translational Oncology, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Early Discovery Biochemistry, Bernardo, Elizabeth |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research bcl-X Protein Antineoplastic Agents [SDV.CAN]Life Sciences [q-bio]/Cancer Biology Pharmacology Bortezomib Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine [SDV.CAN] Life Sciences [q-bio]/Cancer Downregulation and upregulation immune system diseases Cell Line Tumor hemic and lymphatic diseases medicine Animals Humans Multiple myeloma Sulfonamides Navitoclax Bcl-2-Like Protein 11 Venetoclax Cancer Bridged Bicyclo Compounds Heterocyclic medicine.disease Immunohistochemistry Xenograft Model Antitumor Assays 3. Good health Gene Expression Regulation Neoplastic Disease Models Animal 030104 developmental biology medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 Oncology chemistry Drug Resistance Neoplasm Cell culture 030220 oncology & carcinogenesis Myeloid Cell Leukemia Sequence 1 Protein Drug Therapy Combination Bone marrow Multiple Myeloma Protein Binding medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics Molecular Cancer Therapeutics, American Association for Cancer Research, 2016, ⟨10.1158/1535-7163.MCT-15-0730⟩ Molecular Cancer Therapeutics, 2016, ⟨10.1158/1535-7163.MCT-15-0730⟩ |
| ISSN: | 1535-7163 1538-8514 |
| Popis: | BCL-2 family proteins dictate survival of human multiple myeloma cells, making them attractive drug targets. Indeed, multiple myeloma cells are sensitive to antagonists that selectively target prosurvival proteins such as BCL-2/BCL-XL (ABT-737 and ABT-263/navitoclax) or BCL-2 only (ABT-199/GDC-0199/venetoclax). Resistance to these three drugs is mediated by expression of MCL-1. However, given the selectivity profile of venetoclax it is unclear whether coexpression of BCL-XL also affects antitumor responses to venetoclax in multiple myeloma. In multiple myeloma cell lines (n = 21), BCL-2 is expressed but sensitivity to venetoclax correlated with high BCL-2 and low BCL-XL or MCL-1 expression. Multiple myeloma cells that coexpress BCL-2 and BCL-XL were resistant to venetoclax but sensitive to a BCL-XL–selective inhibitor (A-1155463). Multiple myeloma xenograft models that coexpressed BCL-XL or MCL-1 with BCL-2 were also resistant to venetoclax. Resistance to venetoclax was mitigated by cotreatment with bortezomib in xenografts that coexpressed BCL-2 and MCL-1 due to upregulation of NOXA, a proapoptotic factor that neutralizes MCL-1. In contrast, xenografts that expressed BCL-XL, MCL-1, and BCL-2 were more sensitive to the combination of bortezomib with a BCL-XL selective inhibitor (A-1331852) but not with venetoclax cotreatment when compared with monotherapies. IHC of multiple myeloma patient bone marrow biopsies and aspirates (n = 95) revealed high levels of BCL-2 and BCL-XL in 62% and 43% of evaluable samples, respectively, while 34% were characterized as BCL-2High/BCL-XLLow. In addition to MCL-1, our data suggest that BCL-XL may also be a potential resistance factor to venetoclax monotherapy and in combination with bortezomib. Mol Cancer Ther; 15(5); 1132–44. ©2016 AACR. |
| Databáze: | OpenAIRE |
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