Acquired resistance to PRMT5 inhibition and the consequent collateral sensitivity to paclitaxel are both Stmn2 dependent

Drug resistance is a major hurdle for the efficacy of cancer therapies. Protein arginine methyltransferase 5 (PRMT5) is an epigenetic regulator that is upregulated in most tumor types, and PRMT5 inhibitors (PRMT5i) are now in clinical trials. Here we describe the first model of resistance to PRMT5 inhibition, using cell lines derived from murine Kras-G12D;p53-null lung adenocarcinomas (LUAD). Initially, PRMT5 inhibition induced proliferation defects and apoptosis, but eventually we were able to generate numerous independent PRMT5i resistant lines. Resistance was drug-induced, not preexisting, and reflects a novel, shared transcriptional state. This state is stable, and it creates a collateral sensitivity to the taxane, paclitaxel. Accordingly, PRMT5i and paclitaxel synergistically suppress Kras-G12D;p53-null murine LUAD cells. Remarkably, a single gene Stathmin 2 (Stmn2) is required for both PRMT5i resistance and paclitaxel sensitivity. Finally, analysis of TCGA patient data showed that high Stmn2 levels correlates with good tumor responses to taxane treatment. Overall design: Three replicates each of Kras/P53 mouse lung adenocarcinoma cells parental (KP1) untreated (N) and treated (Y) with EPZ015666 and 3 untreated resistant lines (R3, R6 and R7).