Kral, Alexander J, Jia, Lu, Sim, GeunYoung, Wan, Ledong, Ishigami, Yuma, Krainer, Adrian R (December 2025) Splice-switching ASOs targeting the AURKA 5' UTR collapse an SRSF1-AURKA-MYC oncogenic circuit in pancreatic cancer. Molecular Cell. S1097-2765(25)00978. ISSN 1097-2765
Abstract
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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL labs > Krainer lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 30 December 2025 |
| Date Deposited: | 05 Jan 2026 15:24 |
| Last Modified: | 05 Jan 2026 15:24 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42052 |
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