HPV-mediated PARP1 regulation and drug sensitization in head and neck cancer

Human Papillomavirus (HPV)-positive Head and Neck (HNC) cancer responds better to radiotherapy and platinum-based chemotherapy than HPV-negative HNC, likely due to impaired DNA damage repair. Inhibiting PARP1 enhances the effects of radiation and chemotherapy in tumours with defective DNA repair, such as HPV-positive cancers. In this study we investigated the role of HPV in the upregulation of PARP1, determining HNC cell sensitivity to both olaparib and cisplatin.

PARP1 expression was assessed in HPV-positive and HPV-negative HNC using TCGA data, HNC cell lines and frozen tumour tissue samples from HNC patients. HPV16 expression was modulated by E6/E7 transduction in Human Primary keratinocytes (HK). Sensitivity to the PARP inhibitor olaparib and cisplatin, alone and in combination, was assessed in HNC cell lines.

HPV-positive tumours and cell lines showed upregulated PARP1 expression and activity, mediated by HPV16 oncoproteins. HPV-positive cell lines were more sensitive to olaparib or cisplatin treatment than HPV-negative ones. Combining cisplatin with olaparib synergistically inhibited cell viability in all HNC cell lines tested, regardless of HPV status.

Our study demonstrates that PARP1 is upregulated in HPV-positive HN tumours and cell lines, compared to HPV-negative. Despite the higher sensitivity of HPV-positive HNC cell lines to olaparib and cisplatin compared to HPV-negative cells, the combination of cisplatin with olaparib synergistically inhibits cell viability across all HNC cell lines tested, regardless of HPV status. This combination may allow for reduced drug concentrations, potentially decreasing side effects and enhancing therapeutic efficacy in HN tumours.