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Myeloma

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

Leukemia volume 28, pages 373–383 (2014)Cite this article

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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.

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Acknowledgements

We thank the Flow Cytometry and Cellular Imaging Core Facility, and the Cell Line Characterization Core funded under the M. D. Anderson Cancer Center Support Grant (NCI no. CA16672). This work was supported by a Multiple Myeloma Research Foundation Senior Award (to RZO) and a Multiple Myeloma Research Foundation Research Fellow Award (to CCB). RZO would also like to acknowledge support from the National Cancer Institute in the form of the M. D. Anderson Cancer Center SPORE in Multiple Myeloma (P50 CA142509). We would also like to acknowledge support from the Brock Family Myeloma Research Fund.

Author Contributions

CCB conceived and performed the majority of the experiments, analyzed the data, prepared the figures and wrote the manuscript. RJJ assisted with some experiments and was involved in data analysis and manuscript preparation. VB and HYL provided statistical analyses of mouse xenograft modeling. QB facilitated access to primary samples and provided helpful discussions. IK performed in vivo experiments. HW generated lentiviral constructs. JJS, SKT, RA, MW and DMW facilitated access to primary samples. RZO provided research guidance, supervised the work herein, facilitated access to primary samples and proofed the manuscript.

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Authors and Affiliations

  1. Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    C C Bjorklund, R J Jones, I Kuiatse, H Wang, J Yang, J J Shah, S K Thomas, M Wang, D M Weber & R Z Orlowski

  2. Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    V Baladandayuthapani & H Y Lin

  3. Division of Cancer Medicine, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    R Z Orlowski

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  1. C C Bjorklund
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Correspondence to R Z Orlowski.

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Competing interests

CCB 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. RZO has served on advisory boards for Celgene Corporation, which markets lenalidomide, and also has received research funding and honoraria from Celgene. The remaining authors declare no conflict of interest.

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Bjorklund, C., Baladandayuthapani, V., Lin, H. et al. Evidence of a role for CD44 and cell adhesion in mediating resistance to lenalidomide in multiple myeloma: therapeutic implications. Leukemia 28, 373–383 (2014). https://doi.org/10.1038/leu.2013.174

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