DNA double strand break repair defect and sensitivity to poly ADP-ribose polymerase (PARP) inhibition in human papillomavirus 16-positive head and neck squamous cell carcinoma |
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Authors: | Alice N Weaver Tiffiny S Cooper Marcela Rodriguez Hoa Q Trummell James A Bonner Eben L Rosenthal Eddy S Yang |
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Institution: | 1. Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35249, USA;2. Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35249, USA;3. Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35249, USA;4. Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35249, USA |
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Abstract: | Patients with human papillomavirus-positive (HPV+) head and neck squamous cell carcinomas (HNSCCs) have increased response to radio- and chemotherapy and improved overall survival, possibly due to an impaired DNA damage response. Here, we investigated the correlation between HPV status and repair of DNA damage in HNSCC cell lines. We also assessed in vitro and in vivo sensitivity to the PARP inhibitor veliparib (ABT-888) in HNSCC cell lines and an HPV+ patient xenograft. Repair of DNA double strand breaks (DSBs) was significantly delayed in HPV+ compared to HPV− HNSCCs, resulting in persistence of γH2AX foci. Although DNA repair activators 53BP1 and BRCA1 were functional in all HNSCCs, HPV+ cells showed downstream defects in both non-homologous end joining and homologous recombination repair. Specifically, HPV+ cells were deficient in protein recruitment and protein expression of DNA-Pk and BRCA2, key factors for non-homologous end joining and homologous recombination respectively. Importantly, the apparent DNA repair defect in HPV+ HNSCCs was associated with increased sensitivity to the PARP inhibitor veliparib, resulting in decreased cell survival in vitro and a 10–14 day tumor growth delay in vivo. These results support the testing of PARP inhibition in combination with DNA damaging agents as a novel therapeutic strategy for HPV+ HNSCC. |
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Keywords: | HPV HNSCC DNA repair PARP inhibition |
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