Inhibiting NHEJ in HNSCC cell lines by the ligase IV inhibitor SCR130 has limited radiosensitizing effects.

Radiotherapy (RT) is a relevant treatment for head and neck squamous cell carcinoma (HNSCC) patients but radioresistance, which depends on DNA damage response (DDR), restrains outcome. Therefore, manipulating DDR by small molecule inhibitors (SMI) is a promising treatment option. The main DNA double strand break (DSB) repair mechanisms in healthy mammalian cells are homologous recombination (HR) and non-homologous end joining (NHEJ). It is known that HR is already often impaired in tumors because of cancerous transitions. Therefore, additionally inhibiting NHEJ is a possibility to specifically target tumor cells and spare healthy tissue, which has the alternative DSB repair mechanism available. We treated HNSCC and healthy fibroblast cell lines with 30 µM of the ligase IV inhibitor SCR130 and a single dose of 2 Gy (Gy) ionizing radiation (IR) to investigate the inhibitor's radiosensitizing effect. In short, the effect of SCR130 in combination with IR on cell death, clonogenicity, and DNA damage is limited and highly cell line specific. Nevertheless, SCR130 increases the number of cells in G0/G1 phase concomitant with gained p21 expression consistently. We suggest that SCR130 in combination with IR has anti-proliferative effects, but an escape of the cells by upregulation of ligase IV resulting from the treatment is possible.