PARP1 inhibition radiosensitizes HNSCC cells deficient in homologous recombination by disabling the DNA replication fork elongation response
Metrics: PDF 1067 views | HTML 1085 views | ?
Stephanie Wurster1,*, Fabian Hennes1,*, Ann C. Parplys1, Jasna I. Seelbach1, Wael Y. Mansour1,2, Alexandra Zielinski1, Cordula Petersen3, Till S. Clauditz4, Adrian Münscher5, Anna A. Friedl6,7, Kerstin Borgmann1
1Laboratory of Radiobiology and Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
2Tumor Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
3Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
4Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
5Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
6Department of Radiation Oncology, Ludwig Maximilians University, Munich, Germany
7Clinical Cooperation Group ‘Personalized Radiotherapy of Head and Neck Cancer’, Helmholtz Center Munich, Neuherberg, Germany
*These authors have contributed equally to this work
Kerstin Borgmann, e-mail: email@example.com
Keywords: homologous recombination, PARP1 inhibition, replication stress, ionizing radiation
Received: July 07, 2015 Accepted: December 22, 2015 Published: January 19, 2016
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.