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

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.

Lycorine targets multiple myeloma stem cell‐like cells by inhibition of Wnt/β‐catenin pathway

“…Multiple myeloma benefits from the bone marrow microenvironment (Kim et al ., 2012; Waldschmidt et al ., 2017). It is reported that BMSCs secrete Wnt ligands, which may cause the disruption of Wnt/β‐catenin pathway in MM (Mikesch et al ., 2007).…”

Silencing of LIMD1 promotes proliferation and reverses cell adhesion‑mediated drug resistance in non‑Hodgkin's lymphoma

“…Although standard systemic chemotherapy remains the main therapy option, the emergence of clinical drug resistance usually leads to therapy failure (4,25). It has been documented that the bone marrow microenvironment may provide components necessary for cell survival, growth and the development of acquired multidrug resistance (26)(27)(28)(29). This environment consists of hematopoietic cells, stromal cells and the extracellular matrix.…”

Aptamer Therapeutics in Cancer: Current and Future

“…Pre-clinical models showed that NOX-A12 mobilized white blood cells, hematopoietic stem cells, and progenitor cells in the peripheral blood of mice and healthy human volunteers [ 104 ] and Phase I trials (NCT00976378 [ 187 ] and NCT01194934 [ 188 ]) established its safety profile in healthy volunteers. Pre-clinical models demonstrated that co-treatment of multiple myeloma (MM) cells with NOX-A12 inhibited chemotaxis of MM to bone marrow, inhibiting cell adhesion-mediated drug resistance and sensitizing them to chemotherapy [ 189 ]. NOX-A12 also decreased BM niche microenvironment receptivity to MM cells, halting an essential step in disease progression in mouse models [ 190 ].…”