Cluster of differentiation 44 variant 6 (CD44v6)

CD44v6 is a splice variant of the CD44 cell surface glycoprotein, distinguished by the inclusion of the variant exon 6 in its extracellular domain [1]. It functions as a critical co-receptor for several receptor tyrosine kinases, most notably c-Met and VEGFR-2, facilitating their activation by ligands like hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) [1, 2]. CD44v6 is highly overexpressed in various epithelial malignancies, including squamous cell carcinomas and colorectal cancer, where it promotes tumor cell migration, invasion, and metastasis [3, 5]. It is also recognized as a marker for cancer stem cells, contributing to chemoresistance and disease progression [3]. Therapeutic strategies targeting the CD44v6 extracellular domain include monoclonal antibodies, antibody-drug conjugates (ADCs), and CAR-T cell therapies [2, 4]. However, clinical development has faced significant challenges, such as severe skin toxicity (e.g., toxic epidermal necrolysis), due to the expression of CD44v6 in normal keratinocytes [2]. Despite these safety concerns, CD44v6 remains a high-interest target for precision oncology and the development of next-generation immunotherapies [5].

Other names

CD44 variant 6CD44v6 isoformv6-containing CD44 isoformEpicanExtracellular domain of CD44 variant 6

CD44v6-targeting agents primarily function by binding to the extracellular domain of the CD44 variant 6 isoform, thereby disrupting its role as an essential co-receptor for receptor tyrosine kinases (RTKs) such as c-Met and VEGFR-2 [1, 2]. This blockade prevents the interaction between CD44v6 and its ligands, including hyaluronic acid (HA), hepatocyte growth factor (HGF), and osteopontin, which in turn inhibits downstream oncogenic signaling pathways like MAPK/ERK and PI3K/Akt [1, 3]. Additionally, antibody-drug conjugates (ADCs) like bivatuzumab mertansine utilize the receptor for the targeted delivery and internalisation of cytotoxic payloads, while CAR-T cell therapies induce direct T-cell mediated lysis of CD44v6-expressing malignant cells [2, 4].