xCT Inhibition Depletes CD44v-Expressing Tumor Cells That Are Resistant to EGFR-Targeted Therapy in Head and Neck Squamous Cell Carcinoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-03, Vol.73 (6), p.1855-1866
• Main Authors: YOSHIKAWA, Momoko, TSUCHIHASHI, Kenji, MUKAI, Makio, ASODA, Seiji, KAWANA, Hiromasa, NAKAGAWA, Taneaki, SAYA, Hideyuki, NAGANO, Osamu, ISHIMOTO, Takatsugu, YAE, Toshifumi, MOTOHARA, Takeshi, SUGIHARA, Eiji, ONISHI, Nobuyuki, MASUKO, Takashi, YOSHIZAWA, Kunio, KAWASHIRI, Shuichi
• Format: Article
• Language: English
• Subjects: Amino Acid Transport System y+ - antagonists & inhibitors; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - pathology; Cell Differentiation; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - immunology; Head and Neck Neoplasms - pathology; Humans; Hyaluronan Receptors - immunology; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; Pharmacology. Drug treatments; Receptor, Epidermal Growth Factor - drug effects; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-3609-T

The targeting of antioxidant systems that allow stem-like cancer cells to avoid the adverse consequences of oxidative stress might be expected to improve the efficacy of cancer treatment. Here, we show that head and neck squamous cell carcinoma (HNSCC) cells that express variant isoforms of CD44 (CD44v) rely on the activity of the cystine transporter subunit xCT for control of their redox status. xCT inhibition selectively induces apoptosis in CD44v-expressing tumor cells without affecting CD44v-negative differentiated cells in the same tumor. In contrast to CD44v-expressing undifferentiated cells, CD44v-negative differentiated cells manifest EGF receptor (EGFR) activation and rely on EGFR activity for their survival. Combined treatment with inhibitors of xCT-dependent cystine transport and of EGFR resulted in a synergistic reduction of EGFR-expressing HNSCC tumor growth. Thus, xCT-targeted therapy may deplete CD44v-expressing undifferentiated HNSCC cells and concurrently sensitize the remaining differentiating cells to available treatments including EGFR-targeted therapy.