Abstract
CC-115 is a dual inhibitor of the mechanistic target of rapamycin (mTOR) kinase and the DNA-dependent protein kinase (DNA-PK) that is currently being studied in phase I/II clinical trials. DNA-PK is essential for the repair of DNA-double strand breaks (DSB). Radiotherapy is frequently used in the palliative treatment of metastatic melanoma patients and induces DSBs. Melanoma cell lines and healthy-donor skin fibroblast cell lines were treated with CC-115 and ionizing irradiation (IR). Apoptosis, necrosis, and cell cycle distribution were analyzed. Colony forming assays were conducted to study radiosensitizing effects. Immunofluorescence microscopy was performed to determine the activity of homologous recombination (HR). In most of the malign cell lines, an increasing concentration of CC-115 resulted in increased cell death. Furthermore, strong cytotoxic effects were only observed in malignant cell lines. Regarding clonogenicity, all cell lines displayed decreased survival fractions during combined inhibitor and IR treatment and supra-additive effects of the combination were observable in 5 out of 9 melanoma cell lines. CC-115 showed radiosensitizing potential in 7 out of 9 melanoma cell lines, but not in healthy skin fibroblasts. Based on our data CC-115 treatment could be a promising approach for patients with metastatic melanoma, particularly in the combination with radiotherapy.
Highlights
The stability and integrity of the DNA is substantial for its function
CC-115 is a dual inhibitor of the mechanistic target of rapamycin kinase and the DNA-dependent protein kinase (DNA-PK) that is currently being studied in phase I/II clinical trials
Based on our data CC-115 treatment could be a promising approach for patients with metastatic melanoma, in the combination with radiotherapy
Summary
The stability and integrity of the DNA is substantial for its function. Genomic instability plays a major role in cancer development and is often based on mutations in DNA repair genes [1]. Different inhibitors of DNA-PK have been developed recently [24,25] and are currently evaluated in clinical trials for patients with various malignancies (e.g., NCT02316197, NCT03770689). The anti-tumor effects of CC-115 in vitro have been shown in hepatocellular, breast, head, and neck, as well as hematological and non-small-cell lung cancer [34,35]. Brain metastases represent the main cause of death in melanoma patients [42]. In recent years, targeted therapies such as BRAFMEK inhibitor therapy and immune check point inhibitors with anti-CTLA4/PD-1 antibodies have improved the overall survival of patients with metastatic melanoma [48,49] and the combination of radiotherapy with systemic therapies has been thoroughly evaluated [50,51,52,53]. We noticed strong effects of CC-115 treatment alone and in combination with IR in RERO, ARPA, H18MK, and especially Mel624 cells
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