HSP90 inhibition as a way to treat cancer

Abstract

Master thesis, Programme in medicine. TITLE: HSP90 inhibition as a way to treat cancer. AUTHOR: Christoffer Vannas. Myxoid liposarcoma (MLS) is a rare soft-tissue tumor. An important oncogenic factor driving the tumor is abnormal proliferative signals through tyrosine kinases. Tyrosine kinase inhibitors have been tested as a treatment, but with little effect. An explanation to this might be that different tyrosine kinases can form heterodimers and autophosphorylate each other in the cytoplasm of MLS cells, sustaining a proliferative signal. A protein that can promote this autoactivation process is Heat shock protein 90 (HSP90). HSP90 is a chaperone, a protein involved in modifying misfolded proteins and helping protein complex formation. In tumors, HSP90 has been linked with phosphorylation of tyrosine kinases and promotion of cell proliferation. HSP90 inhibition has been developed as a method to treat cancer. Experiments on mice with MLS and on MLS cell lines have shown that HSP90 inhibition has great potential. The aim of this study was to elucidate the mechanism of HSP90 inhibitions in MLS and the connection to tyrosine kinase signaling, using an HSP90 inhibitor called 17-DMAG. Cultured tumor cells have been analyzed regarding to cell proliferation, expression of target proteins and signaling pathways. The results showed that 17-DMAG diluted in cell medium with 5 % FBS reduced cell proliferation in MLS cell lines. Fibroblasts, used as control cells, were not affected by the drug. Untreated fibroblasts had in general a significantly lower expression of 17-DMAG target proteins than untreated tumor cells. In MLS cell lines, protein quantification showed that activation of tyrosine kinase receptors RET and ErbB3 were reduced after addition of the drug. This indicates that 17-DMAG specifically affects cells dependent on tyrosine kinase signaling, decreasing proliferation and causing cell death. Tyrosine kinase signaling is an important oncogenic factor in myxoid liposarcoma, suggesting that HSP90 inhibition is a possible method for treatment of tumor cells without affecting normal tissue.