Acquired resistance to PRMT5 inhibition induces concomitant collateral sensitivity to paclitaxel

Abstract

<jats:title>Significance</jats:title> <jats:p> Resistance to therapeutics is a challenge when treating cancer patients. Cancer can become resistant to therapies in distinct, unpredictable ways. Therefore, it is important to understand how resistance occurs to enable development of second-line or combination treatment strategies. This study develops cells that are resistant to inhibitors of protein arginine methyltransferase 5 (PRMT5), which is up-regulated in many cancers and being targeted in current clinical trials. We show that resistant lung adenocarcinoma cells are now sensitive to the widely used chemotherapy, paclitaxel, and identify a single gene, <jats:italic>Stmn2</jats:italic> , that is responsible for both the resistance to inhibitors of PRMT5 and the collateral sensitivity to paclitaxel. Our data suggest that combined treatment with PRMT5 inhibitors and taxanes could be a success. </jats:p>