Oncotarget

Research Papers:

PARP1 inhibition radiosensitizes HNSCC cells deficient in homologous recombination by disabling the DNA replication fork elongation response

Stephanie Wurster, Fabian Hennes, Ann C. Parplys, Jasna I. Seelbach, Wael Y. Mansour, Alexandra Zielinski, Cordula Petersen, Till S. Clauditz, Adrian Münscher, Anna A. Friedl, Kerstin Borgmann _

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Abstract

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

Correspondence to:

Kerstin Borgmann, e-mail: borgmann@uke.de

Keywords: homologous recombination, PARP1 inhibition, replication stress, ionizing radiation

Received: July 07, 2015     Accepted: December 22, 2015     Published: January 19, 2016

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.

Author Information

Stephanie Wurster

Fabian Hennes

Ann C. Parplys

Jasna I. Seelbach

Wael Y. Mansour

Alexandra Zielinski

Cordula Petersen

Till S. Clauditz

Adrian Münscher

Anna A. Friedl

Kerstin Borgmann
Primary Contact  _


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