Optimized combination of HDACI and TKI efficiently inhibits metabolic activity in renal cell carcinoma and overcomes sunitinib resistance

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Article number3172
Pages (from-to)1-22
Number of pages22
JournalCancers
Volume12
Issue number11
DOIs
Publication statusPublished - 1 Nov 2020

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