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.
Highlights
Multiple myeloma is a clonal malignancy of B cells that accumulate primarily in the bone marrow
Seven human myeloma cell lines (HMCL) were sensitive to venetoclax based on a mean IC50 1 mmol/L, whereas six of these lines were sensitive to navitoclax, suggesting that they were dependent on BCL-2 for survival (Fig. 1A)
Four HMCLs that were sensitive to navitoclax but resistant to venetoclax were sensitive to A-1155463, suggesting that these lines were dependent on BCL-XL rather than BCL-2 for survival (Fig. 1A)
Summary
The primary aim of our study was to further define expression patterns of BCL-2, BCL-XL, and MCL-1 as biomarkers in HMCLs and multiple myeloma patient samples to refine predictors of response to venetoclax as a single agent and in combination with standardof-care drugs such as bortezomib. Our aim was to correlate tumor sensitivity to venetoclax, initially in cell lines followed by human tumor samples, with the IHC signal intensities observed for BCL-2, BCL-XL, and MCL-1
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