Flash Talk & Poster Presentation 31st Lorne Cancer Conference 2019

Mass cytometric (CyTOF) profiling of cell death in multiple myeloma reveals a new synergy between glucocorticoids and BH3 mimetic drugs (#101)

Charis Teh 1 2 , Melissa E Ko 3 , Jianan Gong 1 2 , David Segal 1 2 , Cassandra J Vandenberg 1 2 , Pasquale L Fedele 1 2 4 , Michael SY Low 1 2 4 , George Grigoriadis 4 5 6 , Andreas Strasser 1 2 , Andrew W Roberts 1 2 7 8 , David CS Huang 1 2 , Garry P Nolan 3 , Daniel HD Gray 1 2
  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  2. The University of Melbourne, Parkville, VIC, Australia
  3. Stanford School of Medicine, CA, USA
  4. Monash Health, Clayton, VIC, Australia
  5. Monash University, Clayton, VIC, Australia
  6. Hudson Institute of Medical Research, Clayton, VIC, Australia
  7. The Royal Melbourne Hospital, Parkville, VIC, Australia
  8. Peter MacCallum Cancer Centre, Parkville, VIC, Australia

Multiple myeloma is an incurable and fatal cancer of immunoglobulin-secreting plasma cells. Current treatments fail because cells that can resist therapy-induced apoptosis arise in patients and cause relapse. To identify the best adjunct targets to improve killing of multiple myeloma cells, we undertook a deep profiling approach using mass cytometry (CyTOF) to simultaneously detect regulators of cell death, cell cycle, cell signaling and cancer-related pathways at the single-cell level following treatment with standard-of-care drugs, dexamethasone or bortezomib.

Time-resolved visualization algorithms combined with machine learning classification models identified a hierarchy of markers that best predict cancer cell death following treatment. We tested these predictions by combining dexamethasone with a novel inhibitor of the top survival factor hit (MCL-1) and observed synergistic killing of multiple myeloma cells lines and naïve patient cells ex vivo. Collectively, these data indicate that deep profiling of cell death responses at the single-cell level can uncover critical cancer cell vulnerabilities and predict synergies between anti-cancer agents. Furthermore, the finding that BH3 mimetics targeting MCL-1 combined with dexamethasone synergize to induce apoptotic cell death of multiple myeloma cells offers a combination that could be explored in clinical trials for the induction of deeper responses.