title: xCT inhibition depletes CD44v-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma.
abstract: 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.
authors: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, School of Medicine, Keio University, Shinjuku-ku, Japan.
authors: Momoko
authors: M
authors: Yoshikawa
authors: Kenji
authors: K
authors: Tsuchihashi
authors: Takatsugu
authors: T
authors: Ishimoto
authors: Toshifumi
authors: T
authors: Yae
authors: Takeshi
authors: T
authors: Motohara
authors: Eiji
authors: E
authors: Sugihara
authors: Nobuyuki
authors: N
authors: Onishi
authors: Takashi
authors: T
authors: Masuko
authors: Kunio
authors: K
authors: Yoshizawa
authors: Shuichi
authors: S
authors: Kawashiri
authors: Makio
authors: M
authors: Mukai
authors: Seiji
authors: S
authors: Asoda
authors: Hiromasa
authors: H
authors: Kawana
authors: Taneaki
authors: T
authors: Nakagawa
authors: Hideyuki
authors: H
authors: Saya
authors: Osamu
authors: O
authors: Nagano
mesh_terms: D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation; D066246:ErbB Receptors / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology*
chemical_list: D027182:Amino Acid Transport System y+; D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; C118895:SLC7A11 protein, human; D066246:ErbB Receptors