CXCL12 and CXCR7 are relevant targets to reverse cell adhesion-mediated drug resistance in multiple myeloma
Johannes M Waldschmidt1, Anna Simon1, Dagmar Wider1
1Department of Haematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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.
Insights
Targeting bone marrow protection overcomes drug resistance in multiple myeloma (MM). Blocking CXCR4 and CXCR7 with NOX-A12 or plerixafor resensitizes MM cells to therapies, improving treatment efficacy.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Cell adhesion-mediated drug resistance (CAM-DR) in the bone marrow (BM) is crucial for multiple myeloma (MM) survival.
- Targeting BM protection mechanisms to enhance anti-myeloma therapies remains an underexplored area.
Purpose of the Study:
- To investigate if bone marrow stroma cells (BMSCs) abrogate the efficacy of novel anti-myeloma agents.
- To determine if CXCL12 antagonists (NOX-A12) or CXCR4 inhibitors (plerixafor) can restore sensitivity to these agents.
Main Methods:
- Co-culture of MM cells with BMSCs, evaluating various anti-myeloma agents alone and in combination with NOX-A12 or plerixafor.
- Verification of CXCR4, CD49d, and CD44 as key mediators of MM cell adhesion to BM.
- Assessment of CXCR7 expression in active MM and the functional impact of CXCR4/CXCR7 inhibition on MM chemotaxis.
Main Results:
- CXCR4, CD49d, and CD44 were confirmed as essential for MM cell adhesion to the BM.
- CXCR7 is highly expressed in active MM.
- Co-treatment with plerixafor or NOX-A12 inhibited MM cell chemotaxis to the BM, resensitizing them to vorinostat, pomalidomide, bortezomib, and carfilzomib.
- A phase I/II study demonstrated NOX-A12's feasibility in combination with bortezomib-dexamethasone.
Conclusions:
- NOX-A12 and plerixafor effectively counteract MM cell adhesion-mediated drug resistance by targeting the CXCR4/CXCL12 axis.
- Inhibition of CXCR4 and CXCR7 represents a viable strategy to resensitize relapsed/refractory multiple myeloma to existing therapies.
- NOX-A12 shows promise as an add-on agent to overcome CAM-DR in multiple myeloma treatment regimens.
