The inhibition of the MRN complex by Mirin radiosensitizes particularly HPV-negative HNSCC cell lines

Head and neck squamous cell carcinoma (HNSCC) is a relevant cancer entity with two main risk factors. Human papilloma virus (HPV)-positive ones are induced by virus infection and generally have a good prognosis due to their chemo- and radiosensitivity. In contrast, HPV-negative HNSCCs are primarily caused by tobacco and alcohol abuse; patients have a poor prognosis resulting in the need of innovative targeted and combinatory treatment options. Therefore, we combined the Mre11-Rad50-Nbs1 (MRN) inhibitor Mirin with ionizing radiation (IR). Our hypothesis is that the inhibition of the cancer cells’ DNA damage response (DDR) by Mirin leads to reduced repair capacity and a radiosensitization of the cancer cells. We investigated the effect of Mirin in combination with IR on five HPV-negative and two HPV-positive HNSCC cell lines and one primary fibroblast cell line - serving as healthy control - in several functional assays. We suggest – on the one hand - that Mirin shows a trend towards radiosensitizing effects regarding cell death, cell cycle distribution, colony formation, and deoxyribonucleic acid (DNA) damage in HPV-negative HNSCC cell lines but not in HPV-positive ones. On the other hand, the healthy control was nearly unaffected by the combinatory treatment which indicates low side effects. It is useful to generate a deeper insight into the underlying cellular mechanisms of Mirin response in future studies and further validate Mirin’s potential radiosensitizing effect in HPV-negative HNSCCs.