Optimized Combination of HDACI and TKI Efficiently Inhibits Metabolic Activity in Renal Cell Carcinoma and Overcomes Sunitinib Resistance

SIMPLE SUMMARY: To ameliorate the situation for kidney cancer patients and to broaden the application of available drugs, we initiated this research to enhance the anti-cancer activity through combination treatment. There is an unmet need for innovative treatment strategies and optimized drug combinations haven proven to be an adequate solution. We identified a four-drug combination of two histone deacetylate and two tyrosine kinase inhibitors that is effective in sunitinib-naïve and -resistant human renal cell carcinoma cells. Through our research, we demonstrated the superior anti-cancer activity of an optimized drug combination in comparison to single drugs, while maintaining a good safety/selectivity profile. We anticipate that the development and use of well-established drug combinations will be enforced offering personalized and more diverse treatment options in clinical conditions. ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is characterized by high histone deacetylase (HDAC) activity triggering both cell motility and the development of metastasis. Therefore, there is an unmet need to establish innovative strategies to advance the use of HDAC inhibitors (HDACIs). We selected a set of tyrosine kinase inhibitors (TKIs) and HDACIs to test them in combination, using the validated therapeutically guided multidrug optimization (TGMO) technique based on experimental testing and in silico data modeling. We determined a synergistic low-dose three-drug combination decreasing the cell metabolic activity in metastatic ccRCC cells, Caki-1, by over 80%. This drug combination induced apoptosis and showed anti-angiogenic activity, both in original Caki-1 and in sunitinib-resistant Caki-1 cells. Through phosphoproteomic analysis, we revealed additional targets to improve the translation of this combination in 3-D (co-)culture systems. Cell–cell and cell–environment interactions increased, reverting the invasive and metastatic phenotype of Caki-1 cells. Our data suggest that our optimized low-dose drug combination is highly effective in complex in vitro settings and promotes the activity of HDACIs.