Radiotherapy is an essential treatment strategy to manage the increasing cases of cancer diseases worldwide. Therefore, ionizing radiation (IR) is applied to induce deoxyribonucleic acid (DNA) damage in the cancer cells causing cell inactivation and stopping cancer cells from further proliferation. However, eucaryotic cells have a complex DNA damage response (DDR) network available to detect and repair genomic alterations. That includes non-homologous end-joining (NHEJ) and homologous recombination (HR), which are the main repair pathways for IR-induced DNA doublestrand breaks (DSB). An entity typically treated with radiotherapy is head and neck squamous cell carcinoma (HNSCC). They can be divided in human papilloma virus (HPV) -induced and HPV-negative cancers, the latter being mainly induced by tobacco and alcohol abuse. HPV-negative patients are less chemo- and radiosensitive than HPV-positive ones, which limits their prognosis. Moreover, clinical parameters and biological characteristics of HNSCC patients differ depending on their HPV-status. However, therapy response in both groups is not fully understand yet and treatment schemes are usually independent from the HPV-status of the patient. Especially for patients with HPVegative tumors improved treatment schemes are urgently needed. A possibility are therapeutics that facilitate radiosensitization of cancer cells and therefore increase the efficacy of established treatment options. This thesis aims to contribute to a better understanding of the different treatment response in HPV-positive and HPV-negative HNSCCs. Moreover, two different molecules were characterized regarding their radiosensitizing potential in HNSCCs to support the development of innovative treatment strategies. The goal was to radiosensitize HNSCC cell lines – especially the radioresistant HPV-negative ones – by combining IR with small molecule inhibitors (SMI) of the DNA repair. Due to the fact that cancer cells usually already acquired mutations in their intrinsic DNA repair pathways while tumorigenesis, they are more dependent on the remaining pathways than the healthy surrounding tissue, which enables specifically radiosensitizing cancer cells while sparing healthy tissue. A cell line panel consisting of five HPV-negative and two HPV-positive HNSCC cell lines was treated with a combination of 2 Gray (Gy) IR and a SMI of the DNA repair. Fibroblast cell lines were included as healthy controls. The two inhibitors SCR130 – inhibiting Ligase IV, a key protein of NHEJ – and Mirin – inhibiting the Mre11-Rad50-Nbs1 (MRN) complex relevant for HR – were compared in several functional assays. SCR130 failed to induce effective radiosensitization and the upregulation of Ligase IV was detected as a possible cellular escape mechanism from the treatment. However, Mirin tended to specifically radiosensitize the HPV-negative cell lines. This thesis gained knowledge about the radiosensitizing effect of SCR130 and Mirin and identified the MRN complex as a promising target for radiosensitization of HPV-negative HNSCC. In the long term, this could contribute to a more personalized treatment of HNSCCs patients taking into account their HPV-status and can support the establishment of innovative treatment strategies using inhibitors of the DNA repair.
Laura Hildebrand (Thu,) studied this question.