Comparative proton and photon irradiation combined with pharmacological inhibitors in 3D pancreatic cancer cultures

Pancreatic ductal adenocarcinoma (PDAC) is a highly therapy resistant tumor entity of unmet need. Over the last decades, radiotherapy has been considered as additional treatment modality to surgery and chemotherapy. Owing to radiosensitive abdominal organs, high precision proton beam radiotherapy has been regarded superior to photon radiotherapy. To further elucidate the potential of combination therapies, we employed a more physiological 3D, matrix-based cell culture model to assess tumoroid formation capacity after photon and proton irradiation. Additionally, we investigated proton and photon irradiation-induced phosphoproteomic changes for identifying clinically exploitable targets. Here, we show that proton irradiation elicits a higher efficacy to reduce 3D PDAC tumoroid formation and a greater extent of phosphoproteome alterations compared with photon irradiation. Targeting of proteins identified in the phosphoproteome that were uniquely altered by protons or photons failed to cause radiation type-specific radiosensitization. Targeting DNA repair proteins associated with non-homologous endjoing, however, revealed a strong radiosensitizing potential independent from the radiation type. In conclusion, our findings suggest proton irradiation to be potentially more effective in PDAC than photons without additional efficacy when combined with DNA repair inhibitors.