title: PARP1 inhibition radiosensitizes HNSCC cells deficient in homologous recombination by disabling the DNA replication fork elongation response.
abstract: 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.
authors.affiliation: Laboratory of Radiobiology and Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Wurster
authors.affiliation: Laboratory of Radiobiology and Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Hennes
authors.affiliation: Laboratory of Radiobiology and Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Parplys
authors.affiliation: Laboratory of Radiobiology and Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jasna I
authors.initials: JI
authors.lastname: Seelbach
authors.affiliation: Laboratory of Radiobiology and Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Tumor Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
authors.forename: Wael Y
authors.initials: WY
authors.lastname: Mansour
authors.affiliation: Laboratory of Radiobiology and Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zielinski
authors.affiliation: Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Cordula
authors.initials: C
authors.lastname: Petersen
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Till S
authors.initials: TS
authors.lastname: Clauditz
authors.affiliation: Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Münscher
authors.affiliation: Department of Radiation Oncology, Ludwig Maximilians University, Munich, Germany.|Clinical Cooperation Group 'Personalized Radiotherapy of Head and Neck Cancer', Helmholtz Center Munich, Neuherberg, Germany.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Friedl
authors.affiliation: Laboratory of Radiobiology and Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Borgmann
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000628:therapy*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000628:therapy*; D059765:Homologous Recombination / Q000235:genetics*; D006801:Humans; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C531550:olaparib
keywords: PARP1 inhibition; homologous recombination; ionizing radiation; replication stress