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Targeting PLK1 Reduces MMP10 to Enhance Radiosensitivity in HPV- Head and Neck Cancer
Julianna Korns1, Maria A Lehn1,2, Shreya Shyamsunder1
1Department of Radiation Oncology, University of Cincinnati, Cincinnati, Ohio.
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.
Insights
Combining PLK1 inhibition with radiation therapy shows promise for treating human papilloma virus-negative head and neck squamous cell carcinoma. This approach targets PLK1 and MMP10 to overcome radiation resistance and improve patient outcomes.
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.
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