Coinhibition of topoisomerase 1 and BRD4-mediated pause release selectively kills pancreatic cancer via readthrough transcription

  • Pancreatic carcinoma lacks effective therapeutic strategies resulting in poor prognosis. Transcriptional dysregulation due to alterations in KRAS and MYC affects initiation, development, and survival of this tumor type. Using patient-derived xenografts of KRAS- and MYC-driven pancreatic carcinoma, we show that coinhibition of topoisomerase 1 (TOP1) and bromodomain-containing protein 4 (BRD4) synergistically induces tumor regression by targeting promoter pause release. Comparing the nascent transcriptome with the recruitment of elongation and termination factors, we found that coinhibition of TOP1 and BRD4 disrupts recruitment of transcription termination factors. Thus, RNA polymerases transcribe downstream of genes for hundreds of kilobases leading to readthrough transcription. This occurs during replication, perturbing replisome progression and inducing DNA damage. The synergistic effect of TOP1 + BRD4 inhibition is specific to cancer cells leaving normal cells unaffected, highlighting the tumor’s vulnerability to transcriptional defects. This preclinical study provides a mechanistic understanding of the benefit of combining TOP1 and BRD4 inhibitors to treat pancreatic carcinomas addicted to oncogenic drivers of transcription and replication.

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Author:Donald P. CameronORCiDGND, Jan GrosserORCiDGND, Swetlana Ladigan-BaduraORCiDGND, Vladislav KuzinGND, Evanthia IliopoulouORCiDGND, Anika WiegardORCiDGND, Hajar BenredjemORCiDGND, Kathryn JacksonORCiDGND, Sven-Thorsten LiffersGND, Smiths LueongORCiDGND, Phyllis F. CheungORCiDGND, Deepak VangalaORCiDGND, Michael PohlORCiDGND, Richard ViebahnORCiDGND, Christian TeschendorfGND, Heiner WoltersORCiDGND, Selami UstaORCiDGND, Keyi GengORCiDGND, Claudia KutterORCiDGND, Marie Asenian-Henriksson, Jens SivekeORCiDGND, Andrea TannapfelORCiDGND, Wolff-Helmut SchmiegelGND, Stephan HahnORCiDGND, Laura BaranelloORCiDGND
Parent Title (English):Science advances
Publisher:American Association for the Advancement of Science
Place of publication:Washington, DC
Document Type:Article
Date of Publication (online):2024/02/29
Date of first Publication:2023/10/13
Publishing Institution:Ruhr-Universität Bochum, Universitätsbibliothek
Tag:Open Access Fonds
Issue:41, Artikel eadg5109
First Page:eadg5109-1
Last Page:eadg5109-23
Article Processing Charge funded by the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of Ruhr-Universität Bochum.
Institutes/Facilities:Medizinische Fakultät, Abteilung für Molekulare Gastroenterologische Onkologie
Dewey Decimal Classification:Technik, Medizin, angewandte Wissenschaften / Medizin, Gesundheit
open_access (DINI-Set):open_access
faculties:Medizinische Fakultät
Licence (English):License LogoCreative Commons - CC BY 4.0 - Attribution 4.0 International