Evidence map›Paper›PMID 40782795›Full record

ArticleCell reports. Medicine2025

Combined MEK and PARP inhibition enhances radiation response in rectal cancer.

Qiyun Xiao, Julian E Riedesser, Theresa Mulholland, Zhenchong Li, Jonas Buchloh, Philipp Albrecht, Xinchen Yang, Moying Li, Nachiyappan Venkatachalam, Olga Skabkina and 26 more

Abstract read
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Article in Cell reports. Medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.

0numbers the graph read from it
0cells of the map it votes in
10citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

10 citing papers in PubMed.

  1. Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

36 authors.

Qiyun XiaoDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
Julian E RiedesserDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Theresa MulhollandDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Zhenchong LiDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jonas BuchlohDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Philipp AlbrechtDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Xinchen YangDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Moying LiDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Nachiyappan VenkatachalamDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Olga SkabkinaDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Anna KlupschDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Ella EichhornDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Li WangDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Sebastian BelleDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Nadine SchulteDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Daniel SchmitzDepartment of Gastroenterology and Infectiology, Helios Kliniken Schwerin, University Campus of Medical School Hamburg (MSH), Schwerin, Germany.
Matthias F FroelichInstitute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Kyrhatii TrikhirhisthitJunior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Erica ValentiniDivision of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Kim E BoonekampDivision of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Yvonne PetersenDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Thilo MierschDivision of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Elke BurgermeisterDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Carsten HerskindDepartment of Radiation Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.
Marlon R VeldwijkDepartment of Radiation Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.
Christoph BrochhausenInstitute of Pathology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Robert IhnatkoDivision of Proteomics of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jeroen KrijgsveldDivision of Proteomics of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ina KurthDivision of Radiooncology/Radiobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
Yuxing ZhuDepartment of Oncology, Third Xiangya Hospital, Central South University, Changsha, China.
Yanni MaDepartment of Oncology, Third Xiangya Hospital, Central South University, Changsha, China.
Ke CaoDepartment of Oncology, Third Xiangya Hospital, Central South University, Changsha, China.
Michael BoutrosDivision of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Human Genetics, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
Matthias P EbertDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany; Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
Tianzuo ZhanDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany; Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany. Electronic address: tianzuo.zhan@medma.uni-heidelberg.de.
Johannes BetgeDepartment of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany; Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Electronic address: j.betge@dkfz.de.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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.

Indexed as

Mitogen-Activated Protein Kinase KinasesPoly(ADP-ribose) Polymerase InhibitorsProtein Kinase InhibitorsRectal NeoplasmsAnimalsCell Line, TumorHumansMAP Kinase Signaling SystemMiceOrganoidsRad51 RecombinaseRadiation ToleranceXenograft Model Antitumor AssaysMitogen-Activated Protein Kinase KinasesPoly(ADP-ribose) Polymerase InhibitorsProtein Kinase InhibitorsRad51 RecombinaseDNA repairdrug combination screenMEK inhibitororganoidsPARP inhibitorRAD51radiation therapyradiosensitizerRAS signalingrectal cancer

Identifiers

PMID40782795
PMCPMC12432356

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