CXCL12 and CXCR7 are relevant targets to reverse cell adhesion-mediated drug resistance in multiple myeloma

Br J Haematol. 2017 Oct;179(1):36-49. doi: 10.1111/bjh.14807. Epub 2017 Jul 2.

Abstract

Cell adhesion-mediated drug resistance (CAM-DR) by the bone marrow (BM) is fundamental to multiple myeloma (MM) propagation and survival. Targeting BM protection to increase the efficacy of current anti-myeloma treatment has not been extensively pursued. To extend the understanding of CAM-DR, we hypothesized that the cytotoxic effects of novel anti-myeloma agents may be abrogated by the presence of BM stroma cells (BMSCs) and restored by addition of the CXCL12 antagonist NOX-A12 or the CXCR4 inhibitor plerixafor. Following this hypothesis, we evaluated different anti-myeloma agents alone, with BMSCs and when combined with plerixafor or NOX-A12. We verified CXCR4, CD49d (also termed ITGA4) and CD44 as essential mediators of BM adhesion on MM cells. Additionally, we show that CXCR7, the second receptor of stromal-derived-factor-1 (CXCL12), is highly expressed in active MM. Co-culture proved that co-treatment with plerixafor or NOX-A12, the latter inhibiting CXCR4 and CXCR7, functionally interfered with MM chemotaxis to the BM. This led to the resensitization of MM cells to the anti-myeloma agents vorinostat and pomalidomide and both proteasome inhibitors bortezomib and carfilzomib. Within a multicentre phase I/II study, NOX-A12 was tested in combination with bortezomib-dexamethasone, underlining the feasibility of NOX-A12 as an active add-on agent to antagonize myeloma CAM-DR.

Keywords: adhesion molecules; drug resistance; multiple myeloma; stem cell mobilizing/homing; stroma cells.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Aptamers, Nucleotide / pharmacology
  • Biomarkers
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Cell Adhesion / drug effects*
  • Cell Line, Tumor
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / metabolism*
  • Chromosome Aberrations
  • Coculture Techniques
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Heterocyclic Compounds / pharmacology
  • Heterocyclic Compounds / therapeutic use
  • Humans
  • Immunophenotyping
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Multiple Myeloma / diagnosis
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism*
  • Neoplasm Staging
  • Oligopeptides / pharmacology
  • Phosphorylation
  • Protein Multimerization
  • Protein Transport
  • Receptors, CXCR / genetics
  • Receptors, CXCR / metabolism*
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism

Substances

  • ACKR3 protein, human
  • Antineoplastic Agents
  • Aptamers, Nucleotide
  • Biomarkers
  • Chemokine CXCL12
  • Heterocyclic Compounds
  • NOX-A12
  • Oligopeptides
  • Receptors, CXCR
  • carfilzomib
  • Mitogen-Activated Protein Kinase 1
  • plerixafor octahydrochloride