XCT inhibition depletes CD44v-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma

Momoko Yoshikawa, Kenji Tsuchihashi, Takatsugu Ishimoto, Toshifumi Yae, Takeshi Motohara, Eiji Sugihara, Nobuyuki Onishi, Takashi Masuko, Kunio Yoshizawa, Shuichi Kawashiri, Makio Mukai, Seiji Asoda, Hiromasa Kawana, Taneaki Nakagawa, Hideyuki Saya, Osamu Nagano

Research output: Contribution to journalArticle

104 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1855-1866
Number of pages12
JournalCancer Research
Volume73
Issue number6
DOIs
Publication statusPublished - 2013 Mar 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Yoshikawa, M., Tsuchihashi, K., Ishimoto, T., Yae, T., Motohara, T., Sugihara, E., Onishi, N., Masuko, T., Yoshizawa, K., Kawashiri, S., Mukai, M., Asoda, S., Kawana, H., Nakagawa, T., Saya, H., & Nagano, O. (2013). XCT inhibition depletes CD44v-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma. Cancer Research, 73(6), 1855-1866. https://doi.org/10.1158/0008-5472.CAN-12-3609-T