ArticleJournal of experimental & clinical cancer research : CR2024
Splicing targeting drugs highlight intron retention as an actionable vulnerability in advanced prostate cancer.
Article in Journal of experimental & clinical cancer research : CR, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 9 citations in OpenAlex.
- Targeting the Androgen Receptor and Associated Cofactors in Prostate Cancer: Novel Approaches and Future Perspectives.International journal of molecular sciences · 2026Review
- Long-read sequencing reveals widespread novel splicing and neojunction-derived neoantigens in nasopharyngeal carcinoma.Genome research · 2026Article
- iMPI: An Integrative Database for MicroProteins Encoded by Intron Retention in Tumors.Proteomics · 2026Article
- Plasma Proteomic Profiling Was Used to Discover a Biochemical Recurrence Prediction Model for Prostate Cancer.Molecular & cellular proteomics : MCP · 2026Article
- Global landscape of protein-coding and long non-coding RNA alternative splicing and regulation in the human esophageal squamous cell carcinoma.Cancer cell international · 2026Article
- HnRNP C binding to invertedScience advances · 2026Article
- Direct and indirect effects of spliceosome disruption compromise gene regulation by nonsense-mediated mRNA decay.RNA biology · 2025Article
- aGenome-scale activation screen reveals lncRNA HNF1A-AS1 promotes pancreatic cancer metastasis through interacting with U2SURP to increase CD44 alternative splicing.Journal of gastroenterology · 2025Article
- Heat shock factor 2 regulates oncogenic gamma-herpesvirus gene expression by remodeling the chromatin at the ORF50 and BZLF1 promoter.PLoS pathogens · 2025Article
- Article
- SNRPB2 promotes triple-negative breast cancer progression by controlling alternative splicing of MDM4 pre-mRNA.Cancer science · 2024Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundAdvanced prostate cancer (PC) is characterized by insensitivity to androgen deprivation therapy and chemotherapy, resulting in poor outcome for most patients. Thus, advanced PC urgently needs novel therapeutic strategies. Mounting evidence points to splicing dysregulation as a hallmark of advanced PC. Moreover, pharmacologic inhibition of the splicing process is emerging as a promising option for this disease.
methodBy using a representative androgen-insensitive PC cell line (22Rv1), we have investigated the genome-wide transcriptomic effects underlying the cytotoxic effects exerted by three splicing-targeting drugs: Pladienolide B, indisulam and THZ531. Bioinformatic analyses were performed to uncover the gene structural features underlying sensitivity to transcriptional and splicing regulation by these treatments. Biological pathways altered by these treatments were annotated by gene ontology analyses and validated by functional experiments in cell models.
resultsAlthough eliciting similar cytotoxic effects on advanced PC cells, Pladienolide B, indisulam and THZ531 modulate specific transcriptional and splicing signatures. Drug sensitivity is associated with distinct gene structural features, expression levels and cis-acting sequence elements in the regulated exons and introns. Importantly, we identified PC-relevant genes (i.e. EZH2, MDM4) whose drug-induced splicing alteration exerts an impact on cell survival. Moreover, computational analyses uncovered a widespread impact of splicing-targeting drugs on intron retention, with enrichment in genes implicated in pre-mRNA 3'-end processing (i.e. CSTF3, PCF11). Coherently, advanced PC cells displayed high sensitivity to a specific inhibitor of the cleavage and polyadenylation complex, which enhances the effects of chemotherapeutic drugs that are already in use for this cancer.
conclusionsOur study uncovers intron retention as an actionable vulnerability for advanced PC, which may be exploited to improve therapeutic management of this currently incurable disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.