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 xCTdependent 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.

Expression of the cancer stem cell markers CD44v6 and ABCG2 in tongue cancer: Effect of neoadjuvant chemotherapy on local recurrence

“…Alternative splicing of exons 6-15 (variant exons 1-10) gives rise to numerous variant forms of CD44 (CD44v), in which an additional segment encoded by one or more of the variant exons is inserted in the extracellular domain of CD44s, which is encoded by exons 1-5 and exons 16-20 (16,42,43). The variant 6 isoform (CD44v6), in particular, is associated with several cancer types but not in somatic cells (15,(18)(19)(20)(21). Moreover, CD44v6 is widely known as a marker of CSCs (18,21,36,(44)(45)(46).…”

“…Moreover, we estimated that not only the mechanism for the closed margin but also the residual cancer cells after NAC were involved in the mode of local recurrence. Most recently, some researchers reported that these residual cancer cells after NAC possess the characteristics of cancer stem cells (CSC) (14,15). Yoshikawa et al (15) showed that CD44-expressing cancer cells in the clinical samples of human head and neck cancers selectively survive and increase in number after NAC.…”

“…Most recently, some researchers reported that these residual cancer cells after NAC possess the characteristics of cancer stem cells (CSC) (14,15). Yoshikawa et al (15) showed that CD44-expressing cancer cells in the clinical samples of human head and neck cancers selectively survive and increase in number after NAC. CD44 is a single-pass type I transmembrane glycoprotein and functions as a cellular adhesion molecule for hyaluronic acid, a major component of the extracellular matrix (16,17 (22).…”

Inhibitory effects of tetrandrine on epidermal growth factor-induced invasion and migration in HT29 human colorectal adenocarcinoma cells

“…In addition, the expression levels of EGFR, HER2 and HER3 were determined in primary tumors of colorectal cancer cells, and corresponded with lymph node metastases and liver metastases (42,43). The dysregulation of human EGFR pathways by the overexpression or constitutive activation promote s tumor processes, angiogenesis and metastasis in several types of human cancer (4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Previous studies have demonstrated that tetrandrine inhibits cell metastasis in 4T1 breast cancer cells (18) and CT26 colorectal cancer cells in vivo (25).…”

“…Abnormal protein activity and/or expression levels of EGFR have been correlated with the etiology of several types of human cancer, including colorectal cancer (4,5), non-small cell lung cancer (6,7), breast cancer (8,9), head and neck squamous cell carcinoma (10,11), pancreatic cancer (12) and brain cancer (13). EGFR-targeted therapy has been validated in human colorectal cancer (14), and the chemotherapeutics include pharmacological agents, including cetuximab (Erbitux), which is an EGFR inhibitor (15).…”