Combining the ras inhibitor salirasib and proteasome inhibitors: A potential treatment for multiple Myeloma

Multiple myeloma (MM) is an incurable disease that develops resistance to chemotherapy. New treatments with thalidomide or bortezomib are partially successful. Drug resistance, differentiation block, and increased survival in MM result from genomic alterations, including high overexpression of cyclin D and fibroblast growth factor receptor 3 (FGFR3) and mutations in NRas. Oncogenic Ras isoforms can be inhibited by the Ras inhibitor farnesylthiosalicylic acid (FTS, salirasib), which also inhibits fibroblast growth factor (FGF)-stimulated Ras activation. Here we compared the effects of FTS on the proliferation of NCIH929 (harboring oncogenic NRas) and of two other MM cell lines, MM.1S and U266, which do not harbor oncogenic NRas. NCIH929 responded significantly better than the other cell lines to FTS treatment. FTS also inhibited FGF-stimulated GTP loading of wild-type NRas, and hence ERK activation, in MM-NCIH929. Gene-expression analysis of FTS-treated NCIH929 cells demonstrated downregulation of FGFR3, and the FGFR3 protein in these cells declined after FTS treatment. Combined treatment with FTS and the proteasome inhibitor MG132 or bortezomib yielded synergistic inhibition of NCIH929 MM cell growth. These data strongly suggest that FGFR3 acts together with NRas to activate the MAPK pathway, and that inhibition of Ras by FTS affects both early Ras-dependent signaling and long-term Ras-dependent control of gene expression and protein translation. We suggest that salirasib be considered, both alone and in combination with proteasome inhibitors, as a potential treatment for MM.