PMID- 23760401 OWN - NLM STAT- MEDLINE DCOM- 20140408 LR - 20220310 IS - 1476-5551 (Electronic) IS - 0887-6924 (Print) IS - 0887-6924 (Linking) VI - 28 IP - 2 DP - 2014 Feb TI - Evidence of a role for CD44 and cell adhesion in mediating resistance to lenalidomide in multiple myeloma: therapeutic implications. PG - 373-83 LID - 10.1038/leu.2013.174 [doi] AB - Resistance of myeloma to lenalidomide is an emerging clinical problem, and though it has been associated in part with activation of Wnt/beta-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/beta-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/beta-catenin suppression by FH535 enhanced the activity of lenalidomide, as did interleukin-6 neutralization with siltuximab. Notably, all-trans retinoic acid (ATRA) downregulated total beta-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. FAU - Bjorklund, C C AU - Bjorklund CC AD - Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. FAU - Baladandayuthapani, V AU - Baladandayuthapani V AD - Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. FAU - Lin, H Y AU - Lin HY AD - Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. FAU - Jones, R J AU - Jones RJ AD - Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. FAU - Kuiatse, I AU - Kuiatse I AD - Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. FAU - Wang, H AU - Wang H AD - Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. FAU - Yang, J AU - Yang J AD - Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. FAU - Shah, J J AU - Shah JJ AD - Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. FAU - Thomas, S K AU - Thomas SK AD - Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. FAU - Wang, M AU - Wang M AD - Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. FAU - Weber, D M AU - Weber DM AD - Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. FAU - Orlowski, R Z AU - Orlowski RZ AD - 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. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - P50 CA142509/CA/NCI NIH HHS/United States GR - CA16672/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20130613 PL - England TA - Leukemia JT - Leukemia JID - 8704895 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Hyaluronan Receptors) RN - 0 (Immunologic Factors) RN - 4Z8R6ORS6L (Thalidomide) RN - 5688UTC01R (Tretinoin) RN - 9004-61-9 (Hyaluronic Acid) RN - F0P408N6V4 (Lenalidomide) SB - IM MH - Animals MH - Antibodies, Monoclonal/pharmacology MH - Antibody-Dependent Cell Cytotoxicity MH - Antineoplastic Agents/*therapeutic use MH - Cell Adhesion/genetics MH - Cell Line, Tumor MH - Disease Models, Animal MH - Drug Resistance, Neoplasm/*genetics MH - Gene Expression MH - Humans MH - Hyaluronan Receptors/*genetics/metabolism MH - Hyaluronic Acid/metabolism MH - Immunologic Factors/*therapeutic use MH - Lenalidomide MH - Mice MH - Multiple Myeloma/*drug therapy/*genetics MH - Protein Binding/drug effects MH - Thalidomide/*analogs & derivatives/therapeutic use MH - Tretinoin/pharmacology MH - Xenograft Model Antitumor Assays PMC - PMC3874423 MID - NIHMS500219 COIS- Disclosure of Conflict of Interest C.C.B was a post-doctoral fellow at M. D. Anderson when these studies were performed, but is currently an employee at Celgene Corporation and holds company stock options. R.Z.O. has served on advisory boards for Celgene Corporation, which markets lenalidomide, and also has received research funding and honoraria from Celgene. EDAT- 2013/06/14 06:00 MHDA- 2014/04/09 06:00 PMCR- 2014/02/07 CRDT- 2013/06/14 06:00 PHST- 2013/01/07 00:00 [received] PHST- 2013/05/08 00:00 [revised] PHST- 2013/05/24 00:00 [accepted] PHST- 2013/06/14 06:00 [entrez] PHST- 2013/06/14 06:00 [pubmed] PHST- 2014/04/09 06:00 [medline] PHST- 2014/02/07 00:00 [pmc-release] AID - leu2013174 [pii] AID - 10.1038/leu.2013.174 [doi] PST - ppublish SO - Leukemia. 2014 Feb;28(2):373-83. doi: 10.1038/leu.2013.174. Epub 2013 Jun 13.