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

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/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-X-L 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-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 coexpressed BCL-2 and MCL-1 due to upregulation of NOXA, a proapoptotic factor that neutralizes MCL-1. In contrast, xenografts 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 = 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. (C) 2016 AACR.