Predictive biomarkers of venetoclax efficacy in myeloma

BCL-2 family proteins dictate survival of human multiple myeloma (MM) cells making them attractive drug targets. Indeed, MM cells are sensitive to antagonists that selectively target pro-survival 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 co-expression of BCL-X_L also affects anti-tumor responses to venetoclax in MM. In MM 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. MM cells that co-express BCL-2 and BCL-X_L were resistant to venetoclax but sensitive to a BCL-X_L selective inhibitor (A-1155463). MM xenograft models that co-expressed BCL-X_L or MCL-1 with BCL-2 were also resistant to venetoclax. Resistance to venetoclax was mitigated by co-treatment with bortezomib in xenografts that co-expressed BCL-2 and MCL-1 due to upregulation of NOXA, a pro-apoptotic 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_Lselective inhibitor (A-1331852) but not with venetoclax co-treatment when compared to monotherapies. Immunohistochemistry of MM 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 suggests that BCL-X_L may also be a potential resistance factor to venetoclax monotherapy and in combination with bortezomib.

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