We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Evidence of a role for CD44 and cell adhesion in mediating resistance to lenalidomide in multiple myeloma: therapeutic implications.
- Authors
Bjorklund, C C; Baladandayuthapani, V; Lin, H Y; Jones, R J; Kuiatse, I; Wang, H; Yang, J; Shah, J J; Thomas, S K; Wang, M; Weber, D M; Orlowski, R Z
- 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.
- Subjects
CELL adhesion; MYELOMA proteins; CATENINS; HYALURONIC acid; DRUG resistance
- Publication
Leukemia (08876924), 2014, Vol 28, Issue 2, p373
- ISSN
0887-6924
- Publication type
Article
- DOI
10.1038/leu.2013.174