Targeting PRMT5 inhibitor-induced adaptation in pancreatic cancer with the RBM39 degrader indisulam
Valentina Spielmann, Jonas Buchloh, Selen Selcen, Carolin Schneider, Shaishavi Jansari, Xin Fang, Ningjun Duan, Engin Demirdizen, Lukas Krauß, Jessica Eggert, Geraldine Siegfried, Sandrine Fedou, Christof Lenz, Lena Wieland, Lena-Christin Conradi, Maximilian Reichert, Volker Ellenrieder, Michael Ghadimi, Marian Grade, Elisabeth Hessmann, Abdel-Majid Khatib, Christian J. Braun, Florian Wegwitz, Dieter Saur, Matthias Wirth, Günter SchneiderAbstract
Pancreatic ductal adenocarcinoma (PDAC) remains a formidable clinical challenge. Next-generation protein arginine methyltransferase 5 (PRMT5) inhibitors show promising clinical results in a subset of PDACs with co-deletion of the tumor suppressor CDKN2A and the methylthioadenosine phosphorylase (MTAP) gene, but resistance limits their efficacy. Our study suggests that compensatory spliceosomal reprogramming contributes to adaptation to PRMT5 inhibition. Through comprehensive molecular profiling, we demonstrate that PRMT5 inhibitors induce upregulation of RNA-binding proteins, including RNA-binding protein 39 (RBM39). We investigated whether this response could be therapeutically leveraged by combining PRMT5 inhibition with Indisulam-mediated RBM39 degradation, which yielded synergistic activity in cellular model systems. The combination strategy significantly enhanced apoptotic cell death and suppressed tumor outgrowth in resistance assays compared to single-agent treatments. Multi-omics analysis revealed concomitant suppression of DNA repair and metabolic pathways. Collectively, our work support spliceosomal rewiring as a candidate adaptive response to PRMT5 inhibition and nominates RBM39 as a candidate therapeutic vulnerability, thereby supporting further evaluation of dual targeting of the splicing machinery.