Targeting PLK1 Reduces MMP10 to Enhance Radiosensitivity in HPV— Head and Neck Cancer

Purpose: Radiotherapy is a key treatment for head and neck squamous cell carcinoma (HNSCC), yet local recurrence remains a challenge, especially in patients with human papilloma virus negative (HPV-) HNSCC. Our studies identify polo-like kinase 1 (PLK1) as a promising target for HNSCC. PLK1 is overexpressed in HNSCC and associated with worse survival. Experimental Design: Onvansertib was used to assess the effect of PLK1 inhibition on cell viability and spheroid growth in HPV-and HPV-positive (HPV+) HNSCC cells. Cell-cycle analysis was done to assess G2/M arrest when combining PLK1 inhibition with radiation. Colony formation and in vivo tumor growth assays were done to evaluate the efficacy of the combination of PLK1 inhibition with radiation. RNA sequencing was done to identify targets of PLK1 after onvansertib treatment. Plk1 siRNA knockdown was used to confirm similar responses seen when inhibiting PLK1 with onvansertib. Results: PLK1 inhibition with onvansertib reduced cell viability and spheroid growth of HPV-HNSCC cells. PLK1 inhibition combined with radiation increased G2/M arrest, decreased colony formation of HPV-HNSCC cells, and reduced tumor growth in vivo. RNA sequencing demonstrated that radiation increased MMP10 expression but PLK1 inhibition reversed this effect in HPV-HNSCC cells. PLK1 inhibition reduced MMP10 activity, and Plk1 siRNA knockdown reduced MMP10 expression in HPV-HNSCC cells. Conclusions: These findings suggest that combining PLK1 inhibition with radiation may improve therapeutic response for HPV-HNSCC via MMP10, offering a novel approach to overcome radiation resistance.