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 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.
Authors
- J. Riedesser
- Sebastian Belle
- Daniel Schmitz (ORCID: https://orcid.org/0000-0002-3273-8435)
- Moying Li (ORCID: https://orcid.org/0000-0002-5960-9350)
- Kyrhatii Trikhirhisthit
- Philipp Albrecht (ORCID: https://orcid.org/0000-0001-7987-658X)
- Johannes Betge (ORCID: https://orcid.org/0000-0001-9549-1866)
- Carsten Herskind (ORCID: https://orcid.org/0000-0001-6554-5907)
- Yanni Ma (ORCID: https://orcid.org/0000-0003-2737-4347)
- Christoph Brochhausen (ORCID: https://orcid.org/0000-0002-6761-0247)
- Theresa Mulholland (ORCID: https://orcid.org/0000-0002-2837-0519)
- Ina Kurth (ORCID: https://orcid.org/0000-0001-9261-5165)
- Jonas Buchloh
- Erica Valentini (ORCID: https://orcid.org/0000-0002-5355-5670)
- Olga Skabkina
- Nadine Schulte (ORCID: https://orcid.org/0009-0002-4729-458X)
- Robert Ihnatko (ORCID: https://orcid.org/0000-0001-5751-3622)
- Elke Burgermeister (ORCID: https://orcid.org/0000-0002-4969-5697)
- Kim E. Boonekamp (ORCID: https://orcid.org/0000-0002-9968-5382)
- Yuxing Zhu (ORCID: https://orcid.org/0000-0002-8757-0676)
- Michael Boutros (ORCID: https://orcid.org/0000-0002-9458-817X)
- Ke Cao (ORCID: https://orcid.org/0000-0001-5392-2306)
- Nachiyappan Venkatachalam (ORCID: https://orcid.org/0000-0003-4293-8278)
- Tianzuo Zhan (ORCID: https://orcid.org/0000-0002-9346-3180)
- Marlon R. Veldwijk (ORCID: https://orcid.org/0000-0002-6821-3489)
- Zhenchong Li (ORCID: https://orcid.org/0000-0002-1411-9382)
- Jeroen Krijgsveld (ORCID: https://orcid.org/0000-0001-7549-9326)
- Anna Klupsch
- Li Wang
- Matthias Ebert (ORCID: https://orcid.org/0000-0001-5713-5465)
- Qiyun Xiao
- Xinchen Yang (ORCID: https://orcid.org/0009-0004-3141-7551)
- Matthias F. Froelich
- Thilo Miersch
- Yvonne Petersen
- Ella Eichhorn
Institutions
- Central South University (CN)
- Sun Yat-sen University (CN)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- MSH Medical School Hamburg – University of Applied Sciences and Medical University (DE)
- Helios Hospital Schwerin (DE)
- Sun Yat-sen University Cancer Center (CN)
- University Medical Centre Mannheim (DE)
- Third Xiangya Hospital (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-08-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102284
- Citations
- 2
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- Deutsche Forschungsgemeinschaft
- Hector Stiftung II