Abstract PO-066: Relationship between KEAP1/NFE2L2 pathway activation and radiation resistance in oral cavity cancer

Abstract

Abstract Radiotherapy (RT) is one of the primary treatment modalities for head and neck squamous cell carcinoma (HNSCC) either in the definitive or the adjuvant setting. Unfortunately, despite therapeutic and technological advances in radiotherapy, some patients will have persistence tumor or develop locoregional failure, resulting in significant morbidity and mortality. Presently, there is no biomarker that can reliably identify HNSCC that is resistant to RT. Recent genomic sequencing studies show that mutations in the KEAP1/NFE2L2 pathway exist in HNSCC. However, very little data is available with regards to the relationship between RT resistance and activating mutation or pathway hyperactivation of this pathway in HNSCC. Moreover, the mechanism by which dysregulation of this pathway can lead to RT resistance in HNSCC is poorly understood. Therefore, the project is aimed to study the relationship between KEAP1/NFE2L2 mutations and patient outcomes in HNSCC. To address this aim, DNA sequencing strategies and tissue microarray (TMA) are used to identify mutations and/or a hyperactivation protein signature of the KEAP1/NFE2L2 oxidative stress pathway in an oral cavity cancer patient cohorts (N = 69[MOU1]) treated with surgery and adjuvant RT. In addition, identified mutations are introduced into HNSCC cell lines and mouse xenografts to study the effect of these mutations on radiation response and to identify the mechanism by which they mediate radiation resistance. Here we find that 6% of oral cavity cancer patients harbor mutation in this pathway, primarily in a hotspot in the NFE2L2 gene. NFE2L2 mutation is associated with 100% in-field recurrence after radiotherapy. Strong co-expression of two downstream targets of this pathway (HO1 and NQO1) in tumor cells on the TMA strongly correlates with NFE2L2 mutation and in-field recurrence after RT. Finally, overexpression of the mutated NFE2L2 gene in HNC cell lines lead to increased ROS and radioresistance. Our findings suggest oral cavity cancers harboring activating mutation or a hyperactivation protein signature of the KEAP1/NFE2L2 pathway are more radioresistant. Work is ongoing to validate these findings in other types of HNSCC and to determine how to enhance radiation effectiveness in mutated tumors. Citation Format: Li Guan, Hongbin Cao, Angela Hui, Shirley Kwok, Vignesh Viswanathan, Dhanya Nambiar, Rie V. Eyben, Brittany Holmes, Christina Kong, Maximilian Diehn, Quynh-Thu Le. Relationship between KEAP1/NFE2L2 pathway activation and radiation resistance in oral cavity cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-066.