PRMT5 inhibitors: Therapeutic potential in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is predominantly driven by mutations in the Kirsten rat sarcoma virus (KRAS) oncogene. Due to the pivotal role of KRAS in PDAC pathogenesis, KRAS inhibitors (KRASi) have recently demonstrated initial signs of clinical efficacy. However, considering currently documented response rates and the resistance development to KRASi, additional targeted therapies are needed. In this context, we provide a summary of recent preclinical and clinical findings on protein arginine methyltransferase 5 (PRMT5) inhibitors (PRMT5i) and their implications for PDAC. PRMT5 has been linked to key oncogenic processes, including epithelial-mesenchymal transition (EMT), MYC and Hippo signaling pathways, glycolysis, and therapy resistance. With further advancements and optimization of PRMT5i-based therapies, these inhibitors hold significant potential as therapeutic agents for PDAC treatment. Therefore, we synthesize the current understanding of PRMT5i and highlight promising directions for future developments in PDAC.