{"doi":"10.1101/2025.04.14.648775","title":"Splice-switching ASOs targeting an Alu-derived exon in the <i>AURKA</i> 5’UTR collapse an SRSF1-AURKA-MYC oncogenic circuit in pancreatic cancer","abstract":"ABSTRACT 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":564711,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1467973,"name":"Jia Lu","orcid":"0000-0001-5084-818X","position":1,"is_corresponding":false},{"id":347231,"name":"GeunYoung Sim","orcid":"0000-0002-4850-6348","position":2,"is_corresponding":false},{"id":830976,"name":"Ledong Wan","orcid":"0000-0002-2450-3986","position":3,"is_corresponding":false},{"id":576318,"name":"Adrian R. Krainer","orcid":"0000-0001-9024-9501","position":4,"is_corresponding":false},{"id":1384915,"name":"Alexander J. Kral","orcid":"0009-0004-5462-0296","position":0,"is_corresponding":true}],"reference_count":98,"raw_metadata":null,"created_at":"2026-07-19T02:56:24.872312Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}