Journal
ONCOTARGET
Volume 6, Issue 29, Pages 26995-27007Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4863
Keywords
HPV; HNSCC; DNA repair; PARP inhibition
Categories
Funding
- Translational Scholar Award from Sidney Kimmel Foundation for Cancer Research
- Center for Clinical and Translational Science (CCTS)
- Council of Center Directors (COCD) Translational Research Intramural Pilot from NIH National Center for Research Resources [5UL1 RR025777-04]
- Comprehensive Cancer Center
- Department of Radiation Oncology at University of Alabama at Birmingham School of Medicine
- UAB PREP Scholar's Program NIH [GM086256]
- [P30 AR048311]
- [P30 AI027767]
- [NIGMS MSTP T32GM008361]
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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 YH2AX 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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