Drug repurposing identifies a synergistic high-order drug combination to treat sunitinib-resistant renal cell carcinoma

We report that in response to combination treatment with a synergistic low-dose four-drug combination, human Caki-1 cells resistant to sunitinib alter their pheno- and genotype. We detected that the metabolism of these cells is altered. Gene expression analysis revealed significant differential expression of genes related to mitosis, apoptosis and cell attachment. We detected regulation changes in enzymes mediating the ceramide and sphingolipid metabolism. The experiments have been designed to analyze the effect of a multidrug combination consisting of Rapta-C, erlotinib, metformin and parthenolide in the human Caki-1 cell line resistant to treatment with the small molecule-based targeted drug sunitinib.

本研究报道：在接受协同低剂量四药联合治疗后，对舒尼替尼（sunitinib）耐药的人Caki-1细胞会发生表型与基因型的改变。本研究检测到该细胞的代谢状态发生了显著改变。基因表达分析结果显示，与有丝分裂、细胞凋亡及细胞黏附相关的基因存在显著差异表达。本研究同时检测到介导神经酰胺与鞘脂代谢的酶的调控模式发生了变化。本实验的设计目标为分析由Rapta-C、厄洛替尼（erlotinib）、二甲双胍（metformin）及小白菊内酯（parthenolide）组成的多药联合方案，对携带舒尼替尼耐药表型的人Caki-1细胞系的作用效果。