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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

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-X L (ABT-737 and ABT-263/navitoclax) or BCL-2 only (ABT-199/GDC-0199/vene-toclax). 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-X L also affects antitumor responses to venetoclax in multiple myeloma. In multiple mye-loma cell lines (n ¼ 21), BCL-2 is expressed but sensitivity to venetoclax correlated with high BCL-2 and low BCL-X L or MCL-1 expression. Multiple myeloma cells that coexpress BCL-2 and BCL-X L were resistant to venetoclax but sensitive to a BCL-X L – selective inhibitor (A-1155463). Multiple myeloma xenograft models that coexpressed BCL-X L or MCL-1 with BCL-2 were also resistant to venetoclax. Resistance to venetoclax was mitigated by cotreatment with bortezomib in xenografts that coex-pressed BCL-2 and MCL-1 due to upregulation of NOXA, a proapoptotic factor that neutralizes MCL-1. In contrast, xeno-grafts that expressed BCL-X L , MCL-1, and BCL-2 were more sensitive to the combination of bortezomib with a BCL-X L selective inhibitor (A-1331852) but not with venetoclax cotreatment when compared with monotherapies. IHC of multiple myeloma patient bone marrow biopsies and aspirates (n ¼ 95) revealed high levels of BCL-2 and BCL-X L in 62% and 43% of evaluable samples, respectively, while 34% were characterized as BCL-2 High /BCL-X L Low. In addition to MCL-1, our data suggest that BCL-X L may also be a potential resistance factor to venetoclax monotherapy and in combination with bortezomib. Mol Cancer Ther; 15(5); 1–13. Ó2016 AACR.
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Submitted on : Wednesday, May 4, 2016 - 10:23:32 AM
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Elizabeth A. Punnoose, Joel D. Leverson, Franklin Peale, Erwin R. Boghaert, Lisa D. Belmont, et al.. 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. Molecular Cancer Therapeutics, American Association for Cancer Research, 2016, ⟨10.1158/1535-7163.MCT-15-0730⟩. ⟨inserm-01311318⟩

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