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Radiosensitization approaches for HPV-positive and HPV-negative head and neck squamous carcinomas.
- Source :
-
International journal of cancer [Int J Cancer] 2020 Feb 15; Vol. 146 (4), pp. 1075-1085. Date of Electronic Publication: 2019 Jul 27. - Publication Year :
- 2020
-
Abstract
- Radiotherapy is one of the most used treatment approaches for head and neck squamous cell carcinoma (HNSCC). Targeted inhibition of DNA repair machinery has the potential to improve treatment response by tailoring treatment to cancer cells lacking specific DNA repair pathways. Human papillomavirus (HPV)-negative and HPV-positive HNSCCs respond differently to radiotherapy treatment, suggesting that different approaches of DNA repair inhibition should be employed for these HNSCC groups. Here, we searched for optimal radiosensitization approaches for HPV-positive and HPV-negative HNSCCs by performing a targeted CRISPR-Cas9 screen. We found that inhibition of base excision repair resulted in a better radiotherapy response in HPV-positive HNSCC, which is correlated with upregulation of genes involved in base excision repair. In contrast, inhibition of nonhomologous end-joining and mismatch repair showed strong effects in both HNSCC groups. We validated the screen results by combining radiotherapy with targeted inhibition of DNA repair in several preclinical models including primary and recurrent patient-derived HNSCC xenografts. These findings underline the importance of stratifying HNSCC patients for combination treatments.<br /> (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
- Subjects :
- Animals
Benzimidazoles administration & dosage
CRISPR-Cas Systems genetics
Cell Line, Tumor
Chemoradiotherapy methods
Chromones administration & dosage
DNA Damage drug effects
DNA Damage radiation effects
DNA Repair drug effects
DNA Repair radiation effects
Female
Head and Neck Neoplasms pathology
Head and Neck Neoplasms virology
Humans
Male
Mice
Middle Aged
Morpholines administration & dosage
Neoplasm Recurrence, Local pathology
Neoplasm Recurrence, Local virology
Papillomaviridae drug effects
Papillomaviridae genetics
Papillomavirus Infections pathology
Papillomavirus Infections virology
Radiotherapy Dosage
Squamous Cell Carcinoma of Head and Neck pathology
Squamous Cell Carcinoma of Head and Neck virology
Treatment Outcome
Xenograft Model Antitumor Assays
Head and Neck Neoplasms therapy
Neoplasm Recurrence, Local therapy
Papillomavirus Infections therapy
Radiation-Sensitizing Agents administration & dosage
Squamous Cell Carcinoma of Head and Neck therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0215
- Volume :
- 146
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- International journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 31283004
- Full Text :
- https://doi.org/10.1002/ijc.32558