Targeting Squalene Epoxidase Confers Metabolic Vulnerability and Overcomes Chemoresistance in HNSCC

Area of Science:

• Oncology
• Biochemistry
• Molecular Biology

Background:

• Cisplatin resistance is a major challenge in treating head and neck squamous cell carcinoma (HNSCC).
• Identifying novel therapeutic targets is crucial for overcoming chemoresistance.

Purpose of the Study:

• To investigate the role of squalene epoxidase (SQLE) in cisplatin resistance and tumorigenesis in HNSCC.
• To elucidate the molecular mechanisms underlying SQLE-mediated chemoresistance.
• To evaluate the therapeutic potential of targeting SQLE in HNSCC.

Main Methods:

• Utilized multiple HNSCC tumor models and an internal patient cohort.
• Performed comprehensive transcriptomic analysis.
• Conducted mechanistic investigations involving protein stabilization, degradation pathways, and lipid raft signaling.
• Employed an Sqle conditional knockout mouse model.
• Assessed the synergistic effects of terbinafine and cisplatin in preclinical settings.

Main Results:

• SQLE was identified as a key driver of chemoresistance and tumorigenesis in HNSCC through a cholesterol-dependent pathway.
• SQLE stabilizes c-Myc by preventing its ubiquitin-mediated degradation, essential for c-Myc transcriptional activity.
• SQLE inhibition disrupts Akt signaling within lipid rafts, leading to c-Myc destabilization.
• SQLE plays a critical role in HNSCC initiation and progression, as shown in knockout models.
• Combination therapy with terbinafine and cisplatin demonstrated potent synergistic effects in inhibiting tumor growth.

Conclusions:

• SQLE is a critical mediator of cisplatin resistance and tumorigenesis in HNSCC via c-Myc regulation.
• Targeting SQLE presents a promising therapeutic strategy for HNSCC.
• Combining SQLE inhibitors like terbinafine with cisplatin offers a potential treatment for cisplatin-unresponsive HNSCC patients.