Targeting the apoptotic machinery has emerged as a promising strategy for treating B cell malignancies. However, a growing challenge in the field is understanding why malignant cells develop resistance to apoptosis-inducing drugs after an initial positive response.
To tackle this problem in multiple myeloma, we deeply profiled cells before and after treatment with two apoptosis-inducing drugs using mass cytometry (CyTOF). The technology enabled simultaneous detection of regulators of cell death, mitosis, cell signaling and cancer-related pathways at the single-cell level. Time-resolved visualization algorithms and machine learning classification models delineated putative cell death trajectories and a hierarchy of parameters that specified myeloma cell survival versus apoptosis following treatment. Among these, increased phosphorylation of the cAMP response element-binding protein (CREB) and amounts of the pro-survival protein, MCL-1, were defining features of cells surviving drug treatment. Consistent with this finding, the combination of an MCL-1 inhibitor with dexamethasone elicited potent synergy in killing myeloma cells from patients.
We have extended this study to deeply profile the apoptosis pathway in patients with two other B cell malignancies – mantle cell lymphoma and chronic lymphocytic lymphoma. The data shed light on the unique life/death decision pathways, revealing why certain patients are sensitive/resistant and offering new new drug combinations that can be explored in clinical trials.