Evidence of a role for CD44 and cell adhesion in mediating resistance to lenalidomide in multiple myeloma: Therapeutic implications

C. C. Bjorklund, V. Baladandayuthapani, H. Y. Lin, R. J. Jones, I. Kuiatse, H. Wang, J. Yang, J. J. Shah, S. K. Thomas, M. Wang, D. M. Weber, R. Z. Orlowski

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Resistance of myeloma to lenalidomide is an emerging clinical problem, and though it has been associated in part with activation of Wnt/β-catenin signaling, the mediators of this phenotype remained undefined. Lenalidomide-resistant models were found to overexpress the hyaluronan (HA)-binding protein CD44, a downstream Wnt/β-catenin transcriptional target. Consistent with a role of CD44 in cell adhesion-mediated drug resistance (CAM-DR), lenalidomide-resistant myeloma cells were more adhesive to bone marrow stroma and HA-coated plates. Blockade of CD44 with monoclonal antibodies, free HA or CD44 knockdown reduced adhesion and sensitized to lenalidomide. Wnt/β-catenin suppression by FH535 enhanced the activity of lenalidomide, as did interleukin-6 neutralization with siltuximab. Notably, all-trans retinoic acid (ATRA) downregulated total β-catenin, cell-surface and total CD44, reduced adhesion of lenalidomide-resistant myeloma cells and enhanced the activity of lenalidomide in a lenalidomide-resistant in vivo murine xenograft model. Finally, ATRA sensitized primary myeloma samples from patients that had relapsed and/or refractory disease after lenalidomide therapy to this immunomodulatory agent ex vivo. Taken together, our findings support the hypotheses that CD44 and CAM-DR contribute to lenalidomide resistance in multiple myeloma, that CD44 should be evaluated as a putative biomarker of sensitivity to lenalidomide, and that ATRA or other approaches that target CD44 may overcome clinical lenalidomide resistance.

Original languageEnglish (US)
Pages (from-to)373-383
Number of pages11
JournalLeukemia
Volume28
Issue number2
DOIs
StatePublished - Feb 2014

Keywords

  • ATRA
  • CD44
  • drug resistance
  • lenalidomide

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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