Deep profiling of apoptotic pathways with mass cytometry identifies a synergistic drug combination for killing myeloma cells
- 27 January 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 27 (7), 2217-2233
- https://doi.org/10.1038/s41418-020-0498-z
Abstract
Multiple myeloma is an incurable and fatal cancer of immunoglobulin-secreting plasma cells. Most conventional therapies aim to induce apoptosis in myeloma cells but resistance to these drugs often arises and drives relapse. In this study, we sought to identify the best adjunct targets to kill myeloma cells resistant to conventional therapies using deep profiling by mass cytometry (CyTOF). We validated probes to simultaneously detect 26 regulators of cell death, mitosis, cell signaling, and cancer-related pathways at the single-cell level following treatment of myeloma cells with dexamethasone or bortezomib. Time-resolved visualization algorithms and machine learning random forest models (RFMs) delineated putative cell death trajectories and a hierarchy of parameters that specified myeloma cell survival versus apoptosis following treatment. Among these parameters, increased amounts of phosphorylated cAMP response element-binding protein (CREB) and the pro-survival protein, MCL-1, were defining features of cells surviving drug treatment. Importantly, the RFM prediction that the combination of an MCL-1 inhibitor with dexamethasone would elicit potent, synergistic killing of myeloma cells was validated in other cell lines, in vivo preclinical models and primary myeloma samples from patients. Furthermore, CyTOF analysis of patient bone marrow cells clearly identified myeloma cells and their key cell survival features. This study demonstrates the utility of CyTOF profiling at the single-cell level to identify clinically relevant drug combinations and tracking of patient responses for future clinical trials.Funding Information
- Department of Health | National Health and Medical Research Council (1089072, 1016701, 1020363, 1113577, 1016701, 1079560)
- Australian-American Fulbright Commission (NA)
- U.S. Department of Defense (NA)
- Northrop Grumman (NA)
This publication has 53 references indexed in Scilit:
- ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing plateletsNature Medicine, 2013
- Single-Cell Mass Cytometry of Differential Immune and Drug Responses Across a Human Hematopoietic ContinuumScience, 2011
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Mitochondria and cell death: outer membrane permeabilization and beyondNature Reviews Molecular Cell Biology, 2010
- Web‐Based Analysis and Publication of Flow Cytometry ExperimentsCurrent Protocols in Cytometry, 2010
- Crosstalk in Inflammation: The Interplay of Glucocorticoid Receptor-Based Mechanisms and Kinases and PhosphatasesEndocrine Reviews, 2009
- ABT-737, an inhibitor of Bcl-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cellsLeukemia, 2007
- The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralizedCancer Cell, 2006
- A novel Bcl-2/Bcl-XL/Bcl-w inhibitor ABT-737 as therapy in multiple myelomaOncogene, 2006
- Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survivalLeukemia, 2005