Sorafenib inhibits cell migration and stroma-mediated bortezomib resistance by interfering B-cell receptor signaling and protein translation in mantle cell lymphoma
Menée in vitro et in vivo, cette étude suggère l'intérêt du sorafenib, seul ou en combinaison avec le bortezomib, pour le traitement d'un lymphome à cellules du manteau
Purpose:We evaluated the antitumoral properties of the multikinase inhibitor sorafenib in mantle cell lymphoma (MCL), an aggressive B-lymphoma for which current therapies have shown limited efficacy. Experimental Design:Sensitivity to sorafenib was analyzed in MCL cell lines and primary samples in the context of BCR stimulation and microenvironment simulation. Sorafenib signaling was characterized by quantitative PCR, western blot, immunofluorescence and protein immunoprecipitation. Migration analysis included flow cytometry counting, actin polymerization assays and siRNA-mediated knockdown of FAK. In vivo antitumor effect of sorafenib and bortezomib was analyzed in MCL xenograft mouse model. Results:Sorafenib rapidly dephosphorylates the BCR-associated kinases, SYK and LYN, as well as FAK, a SRC target involved in focal adhesion. In this line, sorafenib displays strong synergy with the SYK inhibitor, R406. Sorafenib also blocks Mcl-1 and cyclin D1 translation, which promotes an unbalance between pro- and anti-apoptotic proteins and facilitates Bax release from cyclin D1, leading to the induction of mitochondrial apoptosis and caspase-dependent and independent mechanisms. Moreover, sorafenib inhibits MCL cell migration and CXCL12-induced actin polymerization. FAK knockdown partially prevents this inhibitory effect, indicating that FAK is a relevant target of sorafenib. Furthermore, sorafenib enhances the antitumoral effect of bortezomib in a MCL xenograft mouse model, as well as overcomes stroma-mediated bortezomib-resistance in MCL cells. Conclusions:We demonstrate for the first time that sorafenib interferes BCR signaling, protein translation and modulates the microenvironment prosurvival signals in MCL, suggesting that sorafenib, alone or in combination with bortezomib, may represent a promising approach to treat MCL patients.