Identification of PRMT5 as a therapeutic target in cholangiocarcinoma [RNA-seq I]

Cholangiocarcinoma is a very aggressive cancer whose incidence is increasing. Moreover, chemotherapies are little effective and the response to immune checkpoint inhibitors is low. We have identified protein arginine-methyltransferase 5 (PRMT5) as a novel therapeutic target in cholangiocarcinoma. PRMT5-targeting drugs markedly inhibited CCA cells proliferation, synergizing with cisplatin and gemcitabine, and hindered the growth of cholangiocarcinoma organoids. PRMT5 inhibition blunted the expression of oncogenic genes involved in chromatin remodeling and DNA repair, consistently inducing the formation of RNA-loops and promoting DNA damage. Our findings support the evaluation of PRMT5 inhibitors in clinical trials. To study the effect of PRMT5 inhibition in cholangiocarcinoma (CCA), the human CCA cell line HuCCT-1 was treated with PRMT5 inhibitor JNJ-64619178 or vehicle (DMSO) and we then performed gene expression profiling analysis using data obtained from RNA-seq of 3 replicates of each condition.