Identification of lenalidomide resistance pathways in myeloma and targeted resensitization using cereblon replacement, inhibition of STAT3 or targeting of IRF4

Blood Cancer J. 2019 Feb 11;9(2):19. doi: 10.1038/s41408-019-0173-0.


To understand immunomodulatory drug (IMiD) resistance in multiple myeloma (MM), we created isogenic human multiple myeloma cell lines (HMCLs) sensitive and resistant to lenalidomide, respectively. Four HMCLs were demonstrated to be resistant to all IMiDs including lenalidomide, pomalidomide, and CC-220, but not to Bortezomib. In three HMLCs (MM.1.SLenRes, KMS11LenRes and OPM2LenRes), CRBN abnormalities were found, including chromosomal deletion, point mutation, and low CRBN expression. The remaining HMCL, XG1LenRes, showed no changes in CRBN but exhibited CD147 upregulation and impaired IRF4 downregulation after lenalidomide treatment. Depletion of CD147 in XG1LenRes and three additional HMCLs had no significant impact on MM viability and lenalidomide response. Further analysis of XG1LenRes demonstrated increased IL6 expression and constitutive STAT3 activation. Inhibition of STAT3 with a selective compound (PB-1-102) re-sensitized XG1LenRes to lenalidomide. Since XG1LenRes harbors a truncated IRF4 that is not downregulated by lenalidomide, we targeted IRF4/MYC axis with a selective inhibitor of the bromodomain of CBP/EP300 (SGC-CBP30), which restored lenalidomide response in XG1LenRes. This strategy also appeared to be more broadly applicable as SGC-CBP30 could re-sensitize two resistant HMCLs with low but detectable CRBN expression to lenalidomide, suggesting that targeting CBP/E300 is a promising approach to restore IMiD sensitivity in MM with detectable CRBN expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Comparative Genomic Hybridization
  • Cytokines
  • Drug Resistance, Neoplasm* / genetics
  • Gene Expression
  • Humans
  • Immunomodulation / drug effects
  • Interferon Regulatory Factors / antagonists & inhibitors*
  • Lenalidomide / pharmacology*
  • Lenalidomide / therapeutic use
  • Models, Biological
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / genetics
  • Multiple Myeloma / immunology
  • Multiple Myeloma / metabolism*
  • Protein Binding
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • Signal Transduction / drug effects*
  • Ubiquitin-Protein Ligases


  • Adaptor Proteins, Signal Transducing
  • Biomarkers, Tumor
  • CRBN protein, human
  • Cytokines
  • Interferon Regulatory Factors
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • interferon regulatory factor-4
  • Ubiquitin-Protein Ligases
  • Lenalidomide