EGFR overexpression increases radiotherapy response in HPV-positive head and neck cancer through inhibition of DNA damage repair and HPV E6 downregulation
| Autor: | Selvam Thavaraj, Ofra Novoplansky, Main Figures Legends, Bushra Ayaz, Nazanin Namazi Sarvestani, Moshe Elkabets, E. Alsahafi, Mahvash Tavassoli |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research DNA Repair medicine.medical_treatment Cetuximab EGFR signalling Targeted therapy Oropharyngeal squamous cell carcinoma (OPSCC) DNA double strand break Mice 0302 clinical medicine Mice Inbred NOD DNA damage repair Epidermal growth factor receptor Head and neck cancer EGFR inhibitors Radiation biology HPV E6 ErbB Receptors Oncology Head and Neck Neoplasms 030220 oncology & carcinogenesis medicine.drug Human papillomavirus Down-Regulation Context (language use) Cell Line 03 medical and health sciences stomatognathic system Cell Line Tumor otorhinolaryngologic diseases medicine Animals Humans neoplasms P53 Squamous Cell Carcinoma of Head and Neck business.industry Papillomavirus Infections Cancer Oncogene Proteins Viral medicine.disease Head and neck squamous-cell carcinoma stomatognathic diseases HEK293 Cells 030104 developmental biology Cancer research biology.protein business DNA Damage |
| Zdroj: | Alsahafi, E N, Thavaraj, S, Sarvestani, N, Novoplansky, O, Elkabets, M, Ayaz, B & Tavassoli, M 2021, ' EGFR overexpression increases radiotherapy response in HPV-positive head and neck cancer through inhibition of DNA damage repair and HPV E6 downregulation ', Cancer Letters, vol. 498, pp. 80-97 . https://doi.org/10.1016/j.canlet.2020.10.035 |
| ISSN: | 0304-3835 |
| DOI: | 10.1016/j.canlet.2020.10.035 |
| Popis: | High-risk Human Papillomavirus (HPV) infections have recently emerged as an independent risk factor in head and neck squamous cell carcinoma (HNSCC). There has been a marked increase in the incidence of HPV-induced HNSCC subtype, which demonstrates different genetics with better treatment outcome. Despite the favourable prognosis of HPV-HNSCC, the treatment modality, consisting of high dose radiotherapy (RT) in combination with chemotherapy (CT), remains similar to HPV-negative tumours, associated with toxic side effects. Epidermal growth factor receptor (EGFR) is overexpressed in over 80% of HNSCC and correlates with RT resistance. EGFR inhibitor Cetuximab is the only FDA approved targeted therapy for both HNSCC subtypes, however the response varies between HNSCC subtypes. In HPV-negative HNSCC, Cetuximab sensitises HNSCC to RT improving survival rates. To reduce adverse cytotoxicity of CT, Cetuximab has been approved for treatment de-escalation of HPV-positive HNSCC. The results of several recent clinical trials have concluded differing outcome to HPV-negative HNSCC. Here we investigated the role of EGFR in HPV-positive HNSCC response to RT. Remarkably, in HPV-positive HNSCC cell lines and in vivo tumour models, EGFR activation was strongly indicative of increased RT response. In response to RT, EGFR activation induced impairment of DNA damage repair and increased RT response. Furthermore, EGFR was found to downregulate HPV oncoproteinE6 expression and induced p53 activity in response to RT. Collectively, our data uncovers a novel role for EGFR in virally induced HNSCC and highlights the importance of using EGFR-targeted therapies in the context of the genetic makeup of cancer. |
| Databáze: | OpenAIRE |
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