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

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 0372544 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2141 (Electronic) Linking ISSN: 00071048 NLM ISO Abbreviation: Br J Haematol Subsets: MEDLINE

Publication: Oxford : Wiley-Blackwell
Original Publication: Oxford : Blackwell Scientific Publications

Drug Resistance, Neoplasm*; Antineoplastic Agents/*pharmacology ; Cell Adhesion/*drug effects ; Chemokine CXCL12/*metabolism ; Multiple Myeloma/*metabolism ; Receptors, CXCR/*metabolism; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/therapeutic use ; Aptamers, Nucleotide/pharmacology ; Benzylamines ; Biomarkers ; Bone Marrow Cells/drug effects ; Bone Marrow Cells/metabolism ; Cell Line, Tumor ; Chemokine CXCL12/genetics ; Chromosome Aberrations ; Coculture Techniques ; Cyclams ; 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 ; Neoplasm Staging ; Oligopeptides/pharmacology ; Phosphorylation ; Protein Multimerization ; Protein Transport ; Receptors, CXCR/genetics ; Stromal Cells/drug effects ; Stromal Cells/metabolism

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.
(© 2017 John Wiley & Sons Ltd.)

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

0 (ACKR3 protein, human)
0 (Antineoplastic Agents)
0 (Aptamers, Nucleotide)
0 (Benzylamines)
0 (Biomarkers)
0 (Chemokine CXCL12)
0 (Cyclams)
0 (Heterocyclic Compounds)
0 (NOX-A12)
0 (Oligopeptides)
0 (Receptors, CXCR)
72X6E3J5AR (carfilzomib)
EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
S915P5499N (plerixafor)

Date Created: 20170704 Date Completed: 20171009 Latest Revision: 20211204

20231215

10.1111/bjh.14807

28670693