PARP1 inhibition radiosensitizes HNSCC cells deficient in homologous recombination by disabling the DNA replication fork elongation response
Autor: | Jasna Irena Seelbach, Fabian Hennes, Ann Christin Parplys, Wael Y. Mansour, Alexandra Zielinski, Till S. Clauditz, Kerstin Borgmann, Stephanie Wurster, Cordula Petersen, Adrian Münscher, Anna A. Friedl |
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Předmět: |
DNA Replication
0301 basic medicine Radiation-Sensitizing Agents DNA Repair replication stress DNA repair Poly (ADP-Ribose) Polymerase-1 homologous recombination Poly(ADP-ribose) Polymerase Inhibitors Biology Poly (ADP-Ribose) Polymerase Inhibitor Piperazines Olaparib 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine PARP1 PARP1 inhibition Cell Line Tumor Humans Genetics Reporter gene Squamous Cell Carcinoma of Head and Neck DNA replication DNA Replication Fork 030104 developmental biology Oncology chemistry Head and Neck Neoplasms 030220 oncology & carcinogenesis Carcinoma Squamous Cell Cancer research Phthalazines ionizing radiation Homologous recombination Homologous Recombination Ionizing Radiation Parp1 Inhibition Replication Stress Research Paper |
Zdroj: | ResearcherID Oncotarget Oncotarget 7, 9732-9741 (2016) |
Popis: | There is a need to develop new, more efficient therapies for head and neck cancer (HNSCC) patients. It is currently unclear whether defects in DNA repair genes play a role in HNSCCs' resistance to therapy. PARP1 inhibitors (PARPi) were found to be "synthetic lethal" in cancers deficient in BRCA1/2 with impaired homologous recombination. Since tumors rarely have these particular mutations, there is considerable interest in finding alternative determinants of PARPi sensitivity. Effectiveness of combined irradiation and PARPi olaparib was evaluated in ten HNSCC cell lines, subdivided into HR-proficient and HR-deficient cell lines using a GFP-based reporter assay. Both groups were equally sensitive to PARPi alone. Combined treatment revealed stronger synergistic interactions in the HR-deficient group. Because HR is mainly active in S-Phase, replication processes were analyzed. A stronger impact of treatment on replication processes (p = 0.04) and an increased number of radial chromosomes (p = 0.003) were observed in the HR-deficient group. We could show that radiosensitization by inhibition of PARP1 strongly correlates with HR competence in a replication-dependent manner. Our observations indicate that PARP1 inhibitors are promising candidates for enhancing the therapeutic ratio achieved by radiotherapy via disabling DNA replication processes in HR-deficient HNSCCs. |
Databáze: | OpenAIRE |
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