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
Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Leukemia. 2014 Feb;28(2):373-83. doi: 10.1038/leu.2013.174. Epub 2013 Jun 13.
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.
骨髓瘤对来那度胺的耐药性是一个新出现的临床问题，尽管这部分与Wnt/β-连环蛋白信号通路的激活有关，但这种表型的介导因子仍不明确。研究发现，来那度胺耐药模型中透明质酸（HA）结合蛋白CD44过表达，CD44是Wnt/β-连环蛋白的下游转录靶点。与CD44在细胞黏附介导的耐药性（CAM-DR）中的作用一致，来那度胺耐药的骨髓瘤细胞对骨髓基质和HA包被的平板更具黏附性。用单克隆抗体、游离HA阻断CD44或敲低CD44可降低黏附性并增加对来那度胺的敏感性。FH535抑制Wnt/β-连环蛋白可增强来那度胺的活性，用西妥昔单抗中和白细胞介素-6也有同样效果。值得注意的是，全反式维甲酸（ATRA）可下调总β-连环蛋白、细胞表面和总CD44，降低来那度胺耐药骨髓瘤细胞的黏附性，并在来那度胺耐药的体内小鼠异种移植模型中增强来那度胺的活性。最后，ATRA使来那度胺治疗后复发和/或难治性疾病患者的原发性骨髓瘤样本在体外对这种免疫调节剂敏感。综上所述，我们的研究结果支持以下假设：CD44和CAM-DR促成了多发性骨髓瘤对来那度胺的耐药性，CD44应作为来那度胺敏感性的潜在生物标志物进行评估，并且ATRA或其他靶向CD44的方法可能克服临床上的来那度胺耐药性。
