Targeting deregulated kinases has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL). Here, we report that the multikinase inhibitor sorafenib selectively induces apoptosis in the majority of CLL cases, with preference for the IGVH unmutated cases and for lymph node-derived CLL cells. We also show that ERK inhibition by sorafenib in CLL cells is an early but not sustained event, thus downregulation of RAF/MEK/ERK pathway is not a crucial effect of this agent in CLL. Among all the different kinases modulated by sorafenib in CLL cells, the blockage of BCR-associated tyrosine kinases, SRC and SYK, is particularly relevant for its action. In line with this, we demonstrate a strong synergy when combining sorafenib with two pharmacological BCR inhibitors, R406 and dasatinib. Importantly, sorafenib overcomes BCR stimulation as well as the protective effect of the stromal coculture. This compound resensitizes CLL cells cultured with stroma to fludarabine- and bendamustine-induced apoptosis. Furthermore, sorafenib inhibits CLL migration toward CXCL12 and blocks both CXCL12- and BCR-induced FAK activation. All these results indicate that sorafenib could overcome the tumoral microenvironment and might be particularly effective in BCR signaling inhibition in CLL cells with higher migratory potential, especially in high risk patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C199.