Targeting PRMT5 Inhibitor-Induced Adaptation in Pancreatic Cancer with the RBM39 Degrader Indisulam.

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 codeletion 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 with single-agent treatments. Multiomics 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. SIGNIFICANCE: Our study suggests that compensatory spliceosomal reprogramming occurs in response to PRMT5 inhibition. We investigated this vulnerability by combining PRMT5 inhibition with indisulam-mediated RBM39 degradation, which yielded synergistic antitumor activity in selected cellular PDAC models.