Activity of Tyrosine Kinase Inhibitors in Multiple Myeloma.

Tyrosine kinase inhibitors (TKIs) have been successfully introduced for the treatment of cancer. Imatinib, dasatinib and nilotinib target bcr/abl and were found to induce molecular remissions in chronic myeloid leukemia. Imatinib has also been found to be active in other malignancies like gastrointestinal stromal tumors. Sunitinib and sorafenib are multi-targeted tyrosine kinase inhibitors and so far, have shown activity against renal cell carcinoma and other cancers. Gefitinib targets the tyrosine kinase of epidermal growth factor receptor and has been found to be active against some cases of non-small cell lung cancer. There is circumstantial evidence that tyrosine kinases and their receptors (e.g. VEGF, IGF-1 and FGFR3) are active in multiple myeloma. In order to develop new treatments for multiple myeloma (MM), we tested several currently available TKIs for their activity against MM cell lines.

Materials and methods: The a cell lines MC/CAR, ARH77, RPMI 8226, ARP1, JJN3, MM1S, and INA-6 were treated with various concentrations of TKIs and analyzed for cell growth in liquid culture, proliferation, apoptosis, and gene expression pattern screening 14,500 genes using U133A_2 arrays.

Results: Imatinib, nilotinib, dasatinib, gefitinib induced cytotoxicity in most cases at high concentrations (50% inhibitory concentration ≥ 100 μMol), whereas sunitinib and sorafenib were active at lower concentrations (50% IC 1– 5 μMol). The cytoxicity was observed early (within 4 to 24 hours of exposure) and involves apoptosis. Interleukin-6 did not offer protection against the cytotoxicity of sorafenib or sunitinib, however the inhibition of proliferation was more pronounced in low fetal calf serum (2.5 versus 10%). A short-term exposure of the myeloma cell line MM1S to 10 μMol sorafenib resulted in more than 2 fold changes in 283 genes or sequences (175 up, 108 down). If only 10 fold changes are considered, 21 genes or sequences were upregulated (mainly enzymes, regulators and ligands) and 11 downregulated (mainly regulatory proteins, among them IL6 signal transducer).

Conclusion: We found that the multitargeted TKIs sorafenib and sunitinib are active in vitro against multiple myeloma. We plan to investigate patient samples, and to elucidate the targets and the mechanisms of action. Our data will support clinical trials both as single agent and in combination with other drugs like bortezomib, thalidomide, alkylators and ionizing radiation.