Tak1-inhibitors are cytotoxic for multiple myeloma cells alone and in combination with melphalan

To determine which genes are affected by NG25 and melphalan, we performed an RNA-seq on INA-6 cells treated with NG25, melphalan or a combination of the two. GSEA focusing on the hallmark pathways showed that melphalan-treatment upregulated genes involved in UV-response, DNA-repair, p53-pathway and TNF-signaling via NF-kB. NG25 induced expression of genes involved in cholesterol homeostasis and mTORC1-signaling and down-regulated MYC- and E2F-targets. MYC is a central driver of MM pathology, and regulate survival as well as cell cycle control through E2F. NG25 reversed the melphalan-induced UV-response. Examination of triplicates of four conditions of multiple myeloma INA-6 cells; control, treated with NG25, treated melphalan, or treated woth both NG25 and melphalan for 6 hours