Single-Cell Proteomics and Tumor RNAseq Identify Novel Pathways Associated With Clofazimine Sensitivity in PI- and IMiD- Resistant Myeloma, and Putative Stem-Like Cells

Harish Kumar, Suman Mazumder, Neeraj Sharma, Sayak Chakravarti, Mark D. Long, Nathalie Meurice, Joachim Petit, Song Liu, Marta Chesi, Sabyasachi Sanyal, A. Keith Stewart, Shaji Kumar, Leif Bergsagel, S. Vincent Rajkumar, Linda B. Baughn, Brian G. Van Ness, Amit Kumar Mitra

Research output: Contribution to journalArticlepeer-review

Abstract

Multiple myeloma (MM) is an incurable plasma cell malignancy with dose-limiting toxicities and inter-individual variation in response/resistance to the standard-of-care/primary drugs, proteasome inhibitors (PIs), and immunomodulatory derivatives (IMiDs). Although newer therapeutic options are potentially highly efficacious, their costs outweigh the effectiveness. Previously, we have established that clofazimine (CLF) activates peroxisome proliferator-activated receptor-γ, synergizes with primary therapies, and targets cancer stem-like cells (CSCs) in drug-resistant chronic myeloid leukemia (CML) patients. In this study, we used a panel of human myeloma cell lines as in vitro model systems representing drug-sensitive, innate/refractory, and clonally-derived acquired/relapsed PI- and cereblon (CRBN)-negative IMiD-resistant myeloma and bone marrow-derived CD138+ primary myeloma cells obtained from patients as ex vivo models to demonstrate that CLF shows significant cytotoxicity against drug-resistant myeloma as single-agent and in combination with PIs and IMiDs. Next, using genome-wide transcriptome analysis (RNA-sequencing), single-cell proteomics (CyTOF; Cytometry by time-of-flight), and ingenuity pathway analysis (IPA), we identified novel pathways associated with CLF efficacy, including induction of ER stress, autophagy, mitochondrial dysfunction, oxidative phosphorylation, enhancement of downstream cascade of p65-NFkB-IRF4-Myc downregulation, and ROS-dependent apoptotic cell death in myeloma. Further, we also showed that CLF is effective in killing rare refractory subclones like side populations that have been referred to as myeloma stem-like cells. Since CLF is an FDA-approved drug and also on WHO’s list of safe and effective essential medicines, it has strong potential to be rapidly re-purposed as a safe and cost-effective anti-myeloma drug.

Original languageEnglish (US)
Article number842200
JournalFrontiers in Oncology
Volume12
DOIs
StatePublished - May 11 2022

Keywords

  • clofazimine
  • CyTOF
  • human myeloma cell lines (HMCLs)
  • immunomodulatory drugs (IMiDs)
  • myeloma
  • proteasome inhibitors (PI)
  • RNAseq
  • side population (SP)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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