title: Evidence of a role for CD44 and cell adhesion in mediating resistance to lenalidomide in multiple myeloma: therapeutic implications.
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.
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Bjorklund
authors.affiliation: Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: V
authors.initials: V
authors.lastname: Baladandayuthapani
authors.affiliation: Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: H Y
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Jones
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: I
authors.initials: I
authors.lastname: Kuiatse
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Shah
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Thomas
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Weber
authors.affiliation: 1] Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA [2] Division of Cancer Medicine, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: R Z
authors.initials: RZ
authors.lastname: Orlowski
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics* / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism; D007155:Immunologic Factors / Q000627:therapeutic use*; D000077269:Lenalidomide; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014212:Tretinoin / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; D007155:Immunologic Factors; D013792:Thalidomide; D014212:Tretinoin; D006820:Hyaluronic Acid; D000077269:Lenalidomide