CD44 antigen isoform 6 (CD44v6)

CD44v6 is a specific splice variant of the CD44 gene, a type I transmembrane glycoprotein that serves as a primary receptor for hyaluronan and a co-receptor for several receptor tyrosine kinases, including MET and VEGFR (UniProt P16070; Orian-Rousseau et al., 2002). The inclusion of variant exon 6 in the extracellular domain distinguishes it from the standard CD44 isoform and enhances its role in promoting oncogenic signaling through the Ras-MAPK and PI3K-Akt pathways (Ponta et al., 2003). CD44v6 is highly expressed in various epithelial and hematological malignancies, such as squamous cell carcinomas, colorectal cancer, and multiple myeloma, where it is associated with tumor invasion, metastasis, and the maintenance of cancer stem cell phenotypes (Todaro et al., 2014; Casucci et al., 2013). Due to its restricted expression in normal tissues compared to standard CD44, it has been extensively explored as a therapeutic target for monoclonal antibodies, antibody-drug conjugates, and CAR-T cell therapies (Sauter et al., 2007; Porcellini et al., 2020). However, its presence in normal skin keratinocytes has led to significant safety challenges, most notably severe dermatological toxicities like toxic epidermal necrolysis, which halted early clinical trials of some agents (Tijink et al., 2006). Current research focuses on developing safer targeting strategies, such as CAR-T cells with inducible safety switches or dual-targeting approaches, to exploit its role as a potent biomarker for poor prognosis and chemoresistance (Heider et al., 2004).

Other names

CD44 variant 6CD44v6EpicanHyaluronate receptorHoming cell adhesion molecule (HCAM)Phagocytic glycoprotein 1 (Pgp-1)Extracellular matrix receptor III (ECMR-III)Ly-24

Inhibition of hyaluronan binding, disruption of MET and VEGFR co-receptor signaling, antibody-dependent cell-mediated cytotoxicity (ADCC), and targeted delivery of cytotoxic payloads or CAR-T cell-mediated direct lysis.