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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Radiotherapy is crucial for head and neck squamous cell carcinoma (HNSCC) but faces challenges with local recurrence, particularly in human papilloma virus-negative (HPV-) HNSCC.
• Polo-like kinase 1 (PLK1) is overexpressed in HNSCC and linked to poorer survival, making it a potential therapeutic target.

Purpose of the Study:

• To investigate the efficacy of PLK1 inhibition, using onvansertib, in combination with radiation therapy for HPV- HNSCC.
• To explore the underlying mechanisms, including the role of MMP10, in the response to combined treatment.

Main Methods:

• Assessed the effects of onvansertib on cell viability and spheroid growth in HPV- and HPV+ HNSCC cells.
• Evaluated G2/M arrest, colony formation, and in vivo tumor growth in response to combined PLK1 inhibition and radiation.
• Utilized RNA-sequencing and siRNA knockdown to identify PLK1 targets and confirm findings, focusing on MMP10 expression and activity.

Main Results:

• PLK1 inhibition with onvansertib reduced viability and spheroid growth in HPV- HNSCC cells.
• The combination of PLK1 inhibition and radiation increased G2/M arrest, reduced colony formation, and inhibited tumor growth in vivo for HPV- HNSCC.
• RNA-sequencing revealed that PLK1 inhibition reversed radiation-induced MMP10 upregulation, and PLK1 inhibition decreased MMP10 activity.

Conclusions:

• Combining PLK1 inhibition with radiation therapy may enhance therapeutic responses in HPV- HNSCC.
• This combination strategy, potentially through modulation of MMP10, offers a novel approach to overcome radioresistance in HNSCC.