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

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.

Novel radiation and targeted therapy combinations for improving rectal cancer outcomes

“…For example, inhibition of ATM using AZ32 or KU-55933 in combination with photon and proton radiation significantly reduced viability of radio-resistant CRC PDOs (Ref. 28). Similarly, inhibition of ATR with AZD6738 with radiation increased the number and cytotoxic capacity of infiltrating CD8+ anti-tumour lymphocytes in an in vivo model of CRC (Ref.…”

Potential Benefits of Combining Proton or Carbon Ion Therapy with DNA Damage Repair Inhibitors

“…Similarly, a study on colorectal cancer organoids with the two ATM inhibitors AZ32 and KU55933 showed roughly similar sensitization to both proton and X-irradiation. Although the LET of protons was not specified in this study, it was likely relatively low, as irradiation was conducted in the middle of the SOBP [ 104 ]. Additionally, a study treating uveal cancer cells with KU55933 in combination with X-rays and low-LET protons (1 keV/µm) also demonstrated comparable sensitization to both types of radiation [ 105 ].…”