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

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.

Cancers. 2020 Oct 28*** epublish ***

Magdalena Rausch, Andrea Weiss, Marloes Zoetemelk, Sander R Piersma, Connie R Jimenez, Judy R van Beijnum, Patrycja Nowak-Sliwinska

Molecular Pharmacology Group, School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva, Switzerland., Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Oncology, Cancer Center Amsterdam, De Boelelaan, 1117 Amsterdam, The Netherlands., Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC-location VUmc, VU University Amsterdam, 1117 Amsterdam, The Netherlands.