Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing.

Here we describe broad anti-proliferative activity of potent, selective, reversible inhibitors of protein arginine methyltransferase5 (PRMT5) including GSK3326595 in human cancer cell lines representing both hematologic and solid malignancies. Interestingly, PRMT5 inhibition activated the p53 pathway via the induction of alternative splicing of MDM4. The MDM4 isoforms witch and subsequent p53 activation are critical determinants of the response to PRMT5 inhibition suggesting that the integrity of the p53-MDM4 regulatory axis defines a subset of patients that could benefit from treatment with GSK3326595. Overall design: RNA-seq from PRMT5 inhibitor treated or control (DMSO) treated lymphoma cell lines performed in duplicate post 3 and 6 days. ** Please note that processed data was generated from control and GSK595 sample pairs and linked to the corresponding GSK595 sample records.