mTOR Inhibition Ablates Cisplatin-Resistant Salivary Gland Cancer Stem Cells

Area of Science:

• Oncology
• Cancer Stem Cell Biology
• Molecular Targeted Therapy

Background:

• Advanced salivary gland mucoepidermoid carcinoma (MEC) has limited treatment options, with current systemic therapies showing poor efficacy.
• Salivary gland cancer stem cells (CSCs) contribute to treatment resistance and tumor progression.
• Platinum-based chemotherapy is largely ineffective against MEC, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate the effect of mechanistic target of rapamycin (mTOR) inhibition on cisplatin resistance in MEC CSCs.
• To evaluate the potential of combining mTOR inhibitors with platinum-based chemotherapy for MEC treatment.

Main Methods:

• Assessed the impact of PI3k/mTOR signaling inhibitors and cisplatin on MEC cell viability using viability assays.
• Examined MEC stemness markers (ALDH, CD44, Bmi-1) and salisphere formation in vitro.
• Evaluated the efficacy of cisplatin and temsirolimus on CSCs in patient-derived xenografts (PDX) in vivo.

Main Results:

• Cisplatin treatment increased mTOR signaling, CSC markers, and salisphere formation in MEC models.
• mTOR inhibition (temsirolimus) counteracted cisplatin-induced stemness and salisphere formation.
• Combined temsirolimus and cisplatin treatment reduced tumor growth and CSC fraction in vivo.

Conclusions:

• Therapeutic inhibition of mTOR effectively targets cytotoxic-resistant CSCs in salivary gland MEC.
• Combining mTOR inhibitors with platinum-based chemotherapy presents a promising strategy for advanced MEC patients.