CISPLATIN RESISTANCE IN HPV-POSITIVE AND HPV-NEGATIVE OROPHARYNGEAL SQUAMOUS CELL CARCINOMA

Background Oropharyngeal squamous cell carcinoma (OPSCC) has 2 clinical subtypes: human papillomavirus (HPV) positive (HPV+) and HPV negative (HPV−). Clinical outcomes in HPV− OPSCC are poor, with a 3-year survival of 57.1%. Although HPV+ has an improved response to therapy (3-year survival of 82.4%), a subset of patients suffered from locoregional recurrences and distant metastases, with a poor prognosis. Therefore, there is a need to understand the molecular basis underlying treatment resistance in both HPV+ and HPV− OPSCC. Objective To generate cisplatin-resistant HPV+ and HPV− OPSCC models in vitro and explore the underlying molecular basis of resistance. Methods HPV+ and HPV− cell lines were exposed to long-term cisplatin treatment to generate resistant models. Immunofluorescence and MTS assays were used to assess DNA double strand breaks and cell viability respectively. RNA sequencing was used to assess differential gene expression between parental and resistant cells. Results The HPV+ and HPV− resistant cells had a significantly higher half-maximal inhibitory concentration (IC50) compared to the parental cells (HPV− resistant cells IC50: 47.5 compared to 10.3 and HPV+ resistant cells IC50: 84.9 compared to 40.0) and showed fewer DNA double strand breaks following cisplatin treatment. Treatment with olaparib partially resensitized both HPV+ and HPV− cells resistant to cisplatin. RNA sequencing showed significant differential gene expression between the parental and resistant cells. Conclusions This study demonstrates novel findings regarding the molecular basis of cisplatin resistance in OPSCC. The findings have implications for future research in this area.