Regulation of nucleotide excision repair by wild-type HRAS signaling in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) is characterized by a high rate of locoregional or distant relapse among patients. It is well established that resistance to chemotherapeutic drugs has an important role in the emergence of the recurrent and/or metastatic type of this malignancy which is associated with poor prognosis. Therefore, understanding the molecular basis of chemoresistance in head and neck cancer is required for the development of effective therapeutic strategies. Activating mutations in the HRAS gene are driver events in human cancer. Although numerous studies have demonstrated that oncogenic HRAS mutations promote chemoresistance in HNSCC, the molecular profile of HNSCC tumors that overexpress wild-type HRAS (wtHRAS^ov) and their response to chemotherapy is poorly investigated. To gain deeper insights into the characteristics of wtHRAS^ov tumors, we conducted a gene expression analysis using transcriptome data from The Cancer Genome Atlas (TCGA). This analysis revealed a distinct signature of overexpressed nucleotide excision repair (NER) genes in wtHRAS^ov tumors, which are associated with chemoresistance. We further explored the role of these NER components in response to genotoxic stress, utilizing a diverse panel of HNSCC cell lines and patient-derived xenografts. Our findings indicate that in a specific cluster of head and neck tumors, ERK/cJun signaling activation is strongly reliant on HRAS activity. Inhibiting HRAS in these tumors results in a significant downregulation of the NER signature components, re-sensitizing cancer cells to platinum-based chemotherapy.