Journal Article

DKFZ-2025-01658

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Combined MEK and PARP inhibition enhances radiation response in rectal cancer.

Xiao, Q. ; Riedesser, J. E. (First author)DKFZ* ; Mulholland, T.DKFZ* ; Li, Z.DKFZ* ; Buchloh, J.DKFZ* ; Albrecht, P.DKFZ* ; Yang, X. ; Li, M. ; Venkatachalam, N. ; Skabkina, O. ; Klupsch, A. ; Eichhorn, E. ; Wang, L. ; Belle, S. ; Schulte, N. ; Schmitz, D. ; Froelich, M. F. ; Trikhirhisthit, K.DKFZ* ; Valentini, E.DKFZ* ; Boonekamp, K. E.DKFZ* ; Petersen, Y.DKFZ* ; Miersch, T.DKFZ* ; Burgermeister, E. ; Herskind, C. ; Veldwijk, M. R. ; Brochhausen, C. ; Ihnatko, R.DKFZ* ; Krijgsveld, J.DKFZ* ; Kurth, I.DKFZ* ; Zhu, Y. ; Ma, Y. ; Cao, K. ; Boutros, M.DKFZ* ; Ebert, M. P. ; Zhan, T. ; Betge, J. (Last author)DKFZ*

2025
Cell Press Cambridge, MA

This record in other databases:  

Please use a persistent id in citations: doi:10.1016/j.xcrm.2025.102284

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.

Keyword(s): DNA repair ; MEK inhibitor ; PARP inhibitor ; RAD51 ; RAS signaling ; drug combination screen ; organoids ; radiation therapy ; radiosensitizer ; rectal cancer

Note: #EA:B440#LA:B440# / 2025 Aug 19;6(8):102284

---

Contributing Institute(s):

1. NWG-KKE Translationale Gastrointestinale Onkologie und präklinische Modelle (B440)
2. B110 Signalwege funktionelle Genomik (B110)
3. B230 Proteomik von Stammzellen und Krebs (B230)
4. E220 Radioonkologie Radiobiologie (E220)
5. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

---

Database coverage:
; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---