Targeting ferroptosis for improved radiotherapy outcomes in HPV-negative head and neck squamous cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Radiotherapy Research

Background:

• Radiotherapy (RT) efficacy is limited in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC).
• Ferroptosis, a regulated cell death pathway, presents a potential therapeutic target.
• Understanding ferroptosis mechanisms is crucial for improving HNSCC treatment outcomes.

Purpose of the Study:

• To identify a ferroptosis-related gene signature (FRGS) predicting outcomes in HPV-negative HNSCC patients treated with RT.
• To investigate the role of specific ferroptosis regulators in HNSCC prognosis.
• To evaluate the potential of statins in combination with RT to overcome radioresistance.

Main Methods:

• Cox proportional hazard modeling was used to develop the FRGS in RT-treated HPV-negative HNSCC patients.
• Gene expression analysis identified key ferroptosis inducers (e.g., NCOA4, NRAMP2/DMT1) and suppressors (e.g., GPX4, FTH1).
• In vitro and in vivo studies assessed the effects of statins (atorvastatin, simvastatin) on ferroptosis induction and radiosensitivity in HNSCC models.

Main Results:

• The developed FRGS significantly predicted overall survival and recurrence-free survival in the studied patient cohort.
• Subtype B of the FRGS, with suppressed ferroptosis, correlated with poorer prognosis.
• Statins demonstrated ferroptosis-inducing properties and enhanced the radiosensitivity of radioresistant HNSCC cells.
• Combination therapy of statins and RT significantly reduced tumor initiation in xenograft models.

Conclusions:

• The FRGS serves as a valuable prognostic biomarker for HPV-negative HNSCC patients undergoing RT.
• Targeting ferroptosis, particularly by overcoming its suppression, holds promise for improving HNSCC treatment.
• Statins represent a viable therapeutic strategy to sensitize HNSCC tumors to RT, potentially improving clinical outcomes.