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+ 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 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.