Rapamycin Targets Cancer Stem Cells to Decrease Cisplatin Resistance in a Head and Neck Cancer Mouse Xenograft Model

ABSTRACT Background Cisplatin is a common chemotherapeutic agent for advanced head and neck squamous cell carcinoma (HNSCC), but treatment success is often limited by resistance. Cancer stem cells (CSCs) are known contributors to this cisplatin chemoresistance in HNSCC. The mechanistic target of rapamycin (mTOR) pathway, which is frequently dysregulated in HNSCC, plays a crucial role via the PI3K/AKT/mTOR axis in maintaining CSC populations and promoting cancer proliferation. However, the specific effects of combining rapamycin, an mTOR pathway inhibitor, with chemotherapeutic agents on CSC maintenance and overall tumorigenicity remain unclear. Methods We examined CSC gene expression in HNSCC cell lines (HSC4, SCC25, OT‐1109) and evaluated the therapeutic potential of combining rapamycin, an mTOR pathway inhibitor, with cisplatin on CSC using a cell viability assay. The combination was further evaluated in an HSC4 mouse xenograft model. Tumor volume and animal weight were monitored throughout treatment. Xenograft tissue analysis via immunohistochemistry assessed stem cell markers (CD133 and ALDH1A1), proliferation markers (Ki‐67), and mTOR pathway inhibition (pS6). Results Administration of low‐dose cisplatin enriched the CD133 + cell population but failed to decrease the tumor mass in HNSCC xenografts. In contrast, the combination of cisplatin and rapamycin significantly impeded tumor growth and minimized toxicity, concurrently reducing the population of CD133 + tumor cells. Conclusion These findings suggest that rapamycin enhances the mechanistic efficacy of cisplatin by specifically targeting and reducing cisplatin‐induced stemness (CD133 + CSC population). This study proposes a viable combination therapy for HNSCC involving an mTOR inhibitor and a platinum‐based drug to overcome CSC‐mediated resistance.