Donald P. Cameron, Jan Grosser, Swetlana Ladigan-Badura, Vladislav Kuzin, Evanthia Iliopoulou, Anika Wiegard, Hajar Benredjem, Kathryn Jackson, Sven-Thorsten Liffers, Smiths Lueong, Phyllis F. Cheung, Deepak Vangala, Michael Pohl, Richard Viebahn, Christian Teschendorf, Heiner Wolters, Selami Usta, Keyi Geng, Claudia Kutter, Marie Asenian-Henriksson, Jens Siveke, Andrea Tannapfel, Wolff-Helmut Schmiegel, Stephan Hahn, Laura Baranello
- 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.
MetadatenAuthor: | 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 |
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URN: | urn:nbn:de:hbz:294-109748 |
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DOI: | https://doi.org/10.1126/sciadv.adg5109 |
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Parent Title (English): | Science advances |
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Publisher: | American Association for the Advancement of Science |
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Place of publication: | Washington, DC |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2024/02/29 |
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Date of first Publication: | 2023/10/13 |
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Publishing Institution: | Ruhr-Universität Bochum, Universitätsbibliothek |
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Tag: | Open Access Fonds |
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Volume: | 9 |
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Issue: | 41, Artikel eadg5109 |
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First Page: | eadg5109-1 |
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Last Page: | eadg5109-23 |
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Note: | Article Processing Charge funded by the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of Ruhr-Universität Bochum. |
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Institutes/Facilities: | Medizinische Fakultät, Abteilung für Molekulare Gastroenterologische Onkologie |
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Dewey Decimal Classification: | Technik, Medizin, angewandte Wissenschaften / Medizin, Gesundheit |
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open_access (DINI-Set): | open_access |
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faculties: | Medizinische Fakultät |
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Licence (English): | Creative Commons - CC BY 4.0 - Attribution 4.0 International |
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