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Splicing dysregulation is emerging as a hallmark and possible therapeutic target of PDAC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed high-throughput RNA sequencing analyses in PANC-1 cells treated with three drugs targeting the U2 small nuclear ribonucleoprotein (U2 snRNP): Pladienolide B, Thailanstatin A and Indisulam. The efficacy of splicing inhibitors, Talazoparib, Alisertib, AZD7762 and Barisertib, alone or in combination, was assessed in PDAC cells and patient-derived organoids (PDOs) by cell viability assays. RT-PCR, western blot and cell cycle assays were performed to evaluate the expression of DNA repair and mitotic genes and the execution of mitosis. PANC-1 cells were engineered to stably co-express GFP-tagged H2b histone and RFP-tagged \u03b2-tubulin by CRISPR\/Cas-9 technology and used for time-lapse confocal microscopy and immunofluorescence analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Genes encoding for the U2 snRNP, which recognizes the 3\u2019 splice site, are upregulated in advanced PDAC. U2 snRNP-targeting drugs impair the DNA damage response (DDR) pathway in homologous recombination-proficient PDAC cells and PDOs, thus enhancing their sensitivity to PARP inhibitors. Genes whose splicing was disrupted by all three drugs are characterized by higher expression, more exon-intron junctions, weak 5\u2019 splice sites and atypical GC content. These features are enriched in mitotic genes (e.g.\n                      <jats:italic>AURKA<\/jats:italic>\n                      ,\n                      <jats:italic>AURKB<\/jats:italic>\n                      ,\n                      <jats:italic>CHEK1<\/jats:italic>\n                      ), whose expression is strongly deregulated by splicing perturbation. Accordingly, splicing inhibition causes severe mitotic defects, leading to the accumulation of cells with misaligned condensed chromosomes on monopolar or bipolar spindles. Notably, high expression of AURKA, AURKB and CHEK1 correlates with poor prognosis in PDAC patients, whereas combined treatments with inhibitors of these mitotic kinases strongly impair the viability of PDAC cells and PDOs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings uncover gene features associated with sensitivity to splicing inhibitors in PDAC cells and suggest that the DDR and mitosis are biological processes highly sensitive to splicing perturbation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03795-3","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T04:49:44Z","timestamp":1785473384000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["U2 snRNP inhibition hampers pancreatic cancer cell viability by disrupting DNA repair proficiency and mitotic checkpoint integrity"],"prefix":"10.1186","volume":"45","author":[{"given":"Valentina","family":"Panzeri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Pieraccioli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Ruta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Vittoria","family":"Manno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Caggiano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duaa","family":"Hartem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Riente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Milletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Quero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Alfieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"L\u00f3pez-Gil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Galv\u00e1n-del-Rey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Guerra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Maulucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Sette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"3795_CR1","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1053\/j.gastro.2022.03.056","volume":"163","author":"LD Wood","year":"2022","unstructured":"Wood LD, Canto MI, Jaffee EM, Simeone DM. 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