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Combined MEK and PARP inhibition enhances radiation response in rectal cancer

Rectal cancer is frequently diagnosed at a locally advanced stage and treated by neoadjuvant chemoradiation. Current efforts to improve treatment outcome are focused on intensifying neoadjuvant chemotherapy, which is associated with higher levels of toxicity. To discover alternative strategies, we e...

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Main Authors: Xiao, Qiyun (Author) , Riedesser, Julian (Author) , Mulholland, Theresa (Author) , Li, Zhenchong (Author) , Buchloh, Jonas (Author) , Albrecht, Philipp (Author) , Yang, Xinchen (Author) , Li, Moying (Author) , Venkatachalam, Nachiyappan (Author) , Skabkina, Olga (Author) , Klupsch, Anna (Author) , Eichhorn, Ella (Author) , Wang, Li (Author) , Belle, Sebastian (Author) , Schulte, Nadine (Author) , Schmitz, Daniel (Author) , Froelich, Matthias F. (Author) , Trikhirhisthit, Kyrhatii (Author) , Valentini, Erica (Author) , Boonekamp, Kim E. (Author) , Petersen, Yvonne (Author) , Miersch, Thilo (Author) , Burgermeister, Elke (Author) , Herskind, Carsten (Author) , Veldwijk, Marlon Romano (Author) , Brochhausen, Christoph (Author) , Ihnatko, Robert (Author) , Krijgsveld, Jeroen (Author) , Kurth, Ina (Author) , Zhu, Yuxing (Author) , Ma, Yanni (Author) , Cao, Ke (Author) , Boutros, Michael (Author) , Ebert, Matthias (Author) , Zhan, Tianzuo (Author) , Betge, Johannes (Author)
Format: Article (Journal)
Language:English
Published: August 19, 2025
In: Cell reports. Medicine
Year: 2025, Volume: 6, Issue: 8, Pages: 1-18, 1-9
ISSN:2666-3791
DOI:10.1016/j.xcrm.2025.102284
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.xcrm.2025.102284
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S266637912500357X
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Author Notes:Qiyun Xiao, Julian E. Riedesser, Theresa Mulholland, Zhenchong Li, Jonas Buchloh, Philipp Albrecht, Xinchen Yang, Moying Li, Nachiyappan Venkatachalam, Olga Skabkina, Anna Klupsch, Ella Eichhorn, Li Wang, Sebastian Belle, Nadine Schulte, Daniel Schmitz, Matthias F. Froelich, Kyrhatii Trikhirhisthit, Erica Valentini, Kim E. Boonekamp, Yvonne Petersen, Thilo Miersch, Elke Burgermeister, Carsten Herskind, Marlon R. Veldwijk, Christoph Brochhausen, Robert Ihnatko, Jeroen Krijgsveld, Ina Kurth, Yuxing Zhu, Yanni Ma, Ke Cao, Michael Boutros, Matthias P. Ebert, Tianzuo Zhan, and Johannes Betge
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Summary:Rectal cancer is frequently diagnosed at a locally advanced stage and treated by neoadjuvant chemoradiation. Current efforts to improve treatment outcome are focused on intensifying neoadjuvant chemotherapy, which is associated with higher levels of toxicity. To discover alternative strategies, we establish patient-derived rectal cancer organoids that reflect clinical radiosensitivity and use these organoids to screen 1,596 drug-radiation combinations. We find that inhibitors of rat sarcoma virus/mitogen-activated protein kinase (RAS-MAPK) signaling, especially mitogen-activated protein kinase kinase (MEK) inhibitors, strongly enhance radiation response. Mechanistically, MEK inhibitors suppress radiation-induced activation of RAS-MAPK signaling and selectively downregulate RAD51, a component of the homologous recombination DNA repair pathway. Through testing drug-drug-radiation combinations in organoids and cell lines, we identify that a combined poly ADP-ribose polymerase (PARP) and MEK inhibition can further enhance radiosensitivity of colorectal cancers, which we confirm in mouse xenograft models. Our data support clinical testing of MEK and PARP combination therapy with radiation in locally advanced rectal cancers as an alternative to chemoradiation.
Item Description:Online verfügbar: 8. August 2025, Artikelversion: 19. August 2025
Gesehen am 01.12.2025
Physical Description:Online Resource
ISSN:2666-3791
DOI:10.1016/j.xcrm.2025.102284

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