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

doi:10.3390/cancers14204984

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

Cancers (Basel). 2022 Oct 11;14(20):4984. doi: 10.3390/cancers14204984.

Authors

Kristin Pape^{1

2}, Anna J Lößner^{1

2}, Doreen William^{3

4

5}, Tabea Czempiel^{3

4

5}, Elke Beyreuther^{6

7}, Anna Klimova², Claudia Lehmann^{1

2}, Tim Schmäche^{1

2}, Sebastian R Merker^{1

2}, Max Naumann^{4

6}, Anne-Marlen Ada^{1

2}, Franziska Baenke^{1

2}, Therese Seidlitz^{1

2}, Rebecca Bütof^{2

6

8

9}, Antje Dietrich^{4

6}, Mechthild Krause^{2

4

6

8

9}, Jürgen Weitz^{1

2}, Barbara Klink^{2

3

4

5

10}, Cläre von Neubeck^{4

6

11}, Daniel E Stange^{1

2}

Affiliations

¹ Department of Visceral, Thoracic and Vascular Surgery, Faculty of Medicine Carl Gustav Carus, University Hospital, Technische Universität Dresden, 01307 Dresden, Germany.
² National Center for Tumor Diseases (NCT/UCC), German Cancer Research Center (DKFZ), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany.
³ Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), Partner Site Dresden, 01307 Dresden, Germany.
⁴ German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁵ Hereditary Cancer Syndrome Center Dresden, ERN-GENTURIS, Institute for Clinical Genetics, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
⁶ OncoRay-National Center for Radiation Research in Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 1307 Dresden, Germany.
⁷ Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiation Physics, 01307 Dresden, Germany.
⁸ Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01307 Dresden, Germany.
⁹ Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
¹⁰ National Center of Genetics (NCG), Laboratoire National de Santé, 3555 Dudelange, Luxembourg.
¹¹ Department of Particle Therapy, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.

Abstract

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.

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

Abstract

Grants and funding