Sorafenib has potent anti-tumor activity in multiple myeloma in vitro, ex vivo and in vivo, in the 5T33MM mouse model
Menée sur des lignées cellulaires, des échantillons prélevés sur des patients atteints d'un myélome multiple et à l'aide d'un modèle murin, cette étude évalue l'activité antitumorale du sorafenib
Multiple Myeloma (MM) is a B-cell malignancy characterized by the expansion of clonal plasma blasts/plasma cells within the bone marrow (BM) that relies on multiple signaling cascades, including tyrosine kinase activated pathways, to proliferate and evade cell death. Despite emerging new treatment strategies, MM remains at present incurable. Thus, novel approaches targeting several signaling cascades by using the multi-tyrosine kinase inhibitor (TKI), sorafenib, seems a promising treatment approach for MM. Here, we demonstrate that sorafenib induces cell death in MM cell lines and in CD138+ enriched primary MM patient samples in a caspase-dependent and independent manner. Furthermore, sorafenib has a strong anti-tumoral and anti-angiogenic activity in the 5T33MM mouse model leading to increased overall survival. MM cells undergo autophagy in response to sorafenib and inhibition of this cytoprotective pathway potentiated the efficacy of this TKI. Mcl-1, a survival factor in MM, is downregulated at the protein level by sorafenib allowing for the execution of cell death, since ectopic overexpression of this protein protects MM cells. Concomitant targeting of Mcl-1 by sorafenib and of Bcl-2/Bcl-xL by the antagonist ABT737 improves the efficacy of sorafenib in MM cell lines and CD138+ enriched primary cells in the presence of BM stromal cells. Altogether, our data support the use of sorafenib as a novel therapeutic modality against human MM and its efficacy maybe potentiated in combination with ABT737.