Sensitization of Patient-Derived Colorectal Cancer Organoids to Photon and Proton Radiation by Targeting DNA Damage Response Mechanisms

Kristin Pape, Anna J. Lößner, Doreen William, Tabea Czempiel, Elke Beyreuther, Anna Klimova, Claudia Lehmann, Tim Schmäche, Sebastian R. Merker, Max Naumann, Anne Marlen Ada, Franziska Baenke, Therese Seidlitz, Rebecca Bütof, Antje Dietrich, Mechthild Krause, Jürgen Weitz, Barbara Klink, Cläre von Neubeck, Daniel E. Stange*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review


Pathological complete response (pCR) has been correlated with overall survival in several cancer entities including colorectal cancer. Novel total neoadjuvant treatment (TNT) in rectal cancer has achieved pathological complete response in one-third of the patients. To define better treatment options for nonresponding patients, we used patient-derived organoids (PDOs) as avatars of the patient’s tumor to apply both photon- and proton-based irradiation as well as single and combined chemo(radio)therapeutic treatments. While response to photon and proton therapy was similar, PDOs revealed heterogeneous responses to irradiation and different chemotherapeutic drugs. Radiotherapeutic response of the PDOs was significantly correlated with their ability to repair irradiation-induced DNA damage. The classical combination of 5-FU and irradiation could not sensitize radioresistant tumor cells. Ataxia-telangiectasia mutated (ATM) kinase was activated upon radiation, and by inhibition of this central sensor of DNA damage, radioresistant PDOs were resensitized. The study underlined the capability of PDOs to define nonresponders to irradiation and could delineate therapeutic approaches for radioresistant patients.

Original languageEnglish
Article number4984
Issue number20
Publication statusPublished - 11 Oct 2022
Externally publishedYes


  • 3D cell culture
  • ATM
  • chemoradiotherapy
  • colorectal cancer
  • DNA damage response
  • patient-derived organoid
  • proton radiation
  • translational radio-oncology


Dive into the research topics of 'Sensitization of Patient-Derived Colorectal Cancer Organoids to Photon and Proton Radiation by Targeting DNA Damage Response Mechanisms'. Together they form a unique fingerprint.

Cite this