Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models.

Abstract

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-2(High)/BCL-XL (Low) 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.

• Authors: Elizabeth A Punnoose, Joel D Leverson, Franklin Peale, Erwin R Boghaert, Lisa D Belmont, Nguyen Tan, Amy Young, Michael Mitten, Ellen Ingalla, Walter C Darbonne, Anatol Oleksijew, Paul Tapang, Peng Yue, Jason Oeh, Leslie Lee, Sophie Maiga, Wayne J Fairbrother, Martine Amiot, Andrew J Souers, Deepak Sampath
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 5 Pg. 1132-44 (05 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 26939706 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Bcl-2-Like Protein 11
• Bridged Bicyclo Compounds, Heterocyclic
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• bcl-X Protein
• Bortezomib
• venetoclax

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Bcl-2-Like Protein 11 (metabolism)
• Bortezomib (pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Drug Therapy, Combination
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Mice
• Multiple Myeloma (drug therapy, genetics, metabolism)
• Myeloid Cell Leukemia Sequence 1 Protein (genetics)
• Protein Binding
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics, metabolism)
• Sulfonamides (pharmacology)
• Xenograft Model Antitumor Assays
• bcl-X Protein (genetics)