American Association for Cancer Research
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Legends for Tables S1 to S3 and Figures S1 to S5 from Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models

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posted on 2023-04-03, 15:43 authored by 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

Legends for Tables S1 to S3 and Figures S1 to S5

Funding

DFG

German Research Foundation

German Cancer Aid

German Federal Ministry of Education and Research

German Cancer Consortium

European Community' Seventh Framework Programme

Pancreatic Cancer Action Network

History

ARTICLE 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-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.