Splice-switching ASOs targeting the AURKA 5' UTR collapse an SRSF1-AURKA-MYC oncogenic circuit in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, driven by oncogenic KRAS mutations and dysregulated oncogenes, including SRSF1, MYC, and Aurora kinase A (AURKA). Although KRAS-targeted therapies are in development, resistance mechanisms underscore the need to identify alternative vulnerabilities. Here, we uncover an SRSF1-AURKA-MYC oncogenic circuit, wherein SRSF1 regulates AURKA 5' UTR alternative splicing, enhancing AURKA protein expression; AURKA positively regulates SRSF1 and MYC post-translationally, independently of its kinase activity; and MYC transcriptionally upregulates both SRSF1 and AURKA. Elevated SRSF1 in tumor cells promotes inclusion of an Alu-derived exon in the AURKA 5' UTR, resulting in splicing-dependent mRNA accumulation and exon-junction-complex deposition. Modulating 5' UTR splicing with splice-switching antisense oligonucleotides (ASOs) collapses the oncogenic circuit, reducing PDAC cell viability and triggering apoptosis. Our findings identify AURKA alternative splicing as a critical regulatory node and highlight a potential therapeutic strategy that simultaneously targets SRSF1, AURKA, and MYC oncogenes.