Dasatinib (BMS-354825): A Multi-Targeted Kinase Inhibitor with Activity Against Multiple Myeloma.

Abstract

The genetic heterogeneity of multiple myeloma (MM) and the evolution of the disease as it progresses result in a multiplicity of proliferative/anti-apoptotic pathways that can operate in MM cells, particularly within the context of their interaction with the bone marrow (BM) microenvironment. Collectively, these factors can contribute to de novo or acquired refractoriness of MM cells to diverse conventional and/or novel anti-MM therapeutics. To counteract the multiplicity of pathways potentially implicated in the control of MM cell resistance to drug-induced apoptosis, we have explored the use of multi-targeted small-molecule inhibitors (e.g. kinase inhibitors), clinical levels of which can simultaneously suppress the expression of multiple targets. Here we describe studies on the novel, oral, multi-targeted kinase inhibitor dasatinib (BMS-354825, Bristol Myers Squibb), which inhibits BCR-ABL, SRC, c-KIT, PDGF-R, and ephrin (EPH) receptor kinases. Although BCR-ABL and c-KIT are not primary oncogenes driving MM proliferation and survival, we studied dasatinib because of: a) emerging data from our laboratory (CS Mitsiades, unpublished observations) on patterns of expression/function patterns of EPH receptors in MM cell lines and primary tumor specimens; and b) the roles of PDGF-R and SRC in tumor-microenvironment interactions, e.g. pericytes/endothelial cells in angiogenesis and osteoclast-mediated bone resorption, respectively. In vitro, we found that dasatinib significantly suppresses, at clinically achievable sub-μM concentrations, the viability of MM cell lines (including lines resistant to conventional or other novel anti-MM agents); primary tumor specimens from multi-drug resistant MM patients; as well as MM cells co-cultured with BM stromal cells. Mechanistic studies showed that dasatinib can induce caspase-8 and -12 activation and sensitize primary MM cells to agents activating caspase-9 (e.g. Dex and bortezomib). Even though IC50 values were higher in MM cells than BCR-ABL+ CML cells, the IC50 of dasatinib was <100 nM in 8/15 MM cell lines tested, suggesting substantial sensitivity to dasatinib in at least a subset of MM. Interim analyses correlating the baseline transcriptional profiles of MM cells with their degree of responsiveness to low nM levels of dasatinib showed that increased responsiveness to this inhibitor correlated with increased baseline expression of diverse proliferative/anti-apoptotic genes, including transcriptional regulators (e.g. MAF, MAFF, NFYC, PML, YY1, DAXX), cell surface receptors (e.g. EPH receptor B4, CXCR4), proteasome subunits (PSMC3, PSMD12, PSME2) and regulators of apoptosis (e.g. CIAP1, IKKe). Ongoing expansion of the panel of tested MM cells is expected to further refine this molecular signature of dasatinib responsiveness. Ongoing in vivo studies are addressing the optimal dose, schedules and sequence of administration of dasatinib in combination with other anti-MM agents. These studies, coupled with our molecular profiling efforts to identify a molecular signature of dasatinib responsiveness, will inform the design of future clinical trials of dasatinib or its analogs for the treatment of MM patients.