TY - JOUR
T1 - EGFR overexpression increases radiotherapy response in HPV-positive head and neck cancer through inhibition of DNA damage repair and HPV E6 downregulation
AU - Alsahafi, Elham Nafea
AU - Thavaraj, Selvam
AU - Sarvestani, Nazanin
AU - Novoplansky, Ofra
AU - Elkabets, Moshe
AU - Ayaz, Bushra
AU - Tavassoli, Mahvash
N1 - Funding Information:
The authors would like to thank Dr Volker Arlt and Dr Halh Al-Serori from MRC-PHE Centre for Environment & Health, King's College London for help in performing Comet assay. Katheryn Begg for helping with radiation experiments. Dr Marcos Jose Custodio Neto Da Silva for helping with HPV-E6 experiments. Leonid Olender, for helping with in-vivo xenograft model's radiation experiments. Elham Nafea Alsahafi is funded by a scholarship from Umm Al-Qura University, Faculty of Dentistry, Makkah City, Saudi Arabia. Grant/Award Number: 4350157921. Ofra Novoplasnky was supported by the Eileen & Louis Dubrovsky Doctoral/Post-Doctoral Cancer Fellowship. We would like to thank the Rosetrees Trust and Stoneygate Trust for supporting this study through grant reference M117-F2 to M.T and the Israeli Cancer Research Foundation (ICRF, 17-1693-RCDA to M.E).
Funding Information:
The authors would like to thank Dr Volker Arlt and Dr Halh Al-Serori from MRC-PHE Centre for Environment & Health, King's College London for help in performing Comet assay. Katheryn Begg for helping with radiation experiments. Dr Marcos Jose Custodio Neto Da Silva for helping with HPV-E6 experiments. Leonid Olender, for helping with in-vivo xenograft model's radiation experiments. Elham Nafea Alsahafi is funded by a scholarship from Umm Al-Qura University , Faculty of Dentistry, Makkah City, Saudi Arabia. Grant/Award Number: 4350157921. Ofra Novoplasnky was supported by the Eileen & Louis Dubrovsky Doctoral/Post-Doctoral Cancer Fellowship. We would like to thank the Rosetrees Trust and Stoneygate Trust for supporting this study through grant reference M117-F2 to M.T and the Israeli Cancer Research Foundation ( ICRF , 17-1693-RCDA to M.E).
Publisher Copyright:
© 2020
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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.
KW - DNA damage repair
KW - DNA double strand break
KW - EGFR signalling
KW - Head and neck cancer
KW - HPV E6
KW - Human papillomavirus
KW - Oropharyngeal squamous cell carcinoma (OPSCC)
KW - P53
KW - Radiation
UR - http://www.scopus.com/inward/record.url?scp=85095587061&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2020.10.035
DO - 10.1016/j.canlet.2020.10.035
M3 - Article
C2 - 33137407
AN - SCOPUS:85095587061
SN - 0304-3835
VL - 498
SP - 80
EP - 97
JO - Cancer Letters
JF - Cancer Letters
ER -
