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April 15th, 2025
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Cold Spring Harbor Laboratory
cancer biology
biorxiv

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

Kral, A. J.Open in Google Scholar•Jia, L.Open in Google Scholar•Sim, G.Open in Google Scholar•Wan, L.Open in Google Scholar•Krainer, A. R.Open in Google Scholar

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, driven by oncogenic KRAS mutations and dysregulated oncogenes, such as SRSF1, MYC, and 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 in turn transcriptionally upregulates both SRSF1 and AURKA. Elevated SRSF1 in tumor cells promotes inclusion of an exonized Alu 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 ASO-mediated splice-switching as a potential therapeutic strategy that simultaneously targets SRSF1, AURKA, and MYC oncogenes.

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