CD44 variant 6 receptor (CD44v6)

CD44 variant 6 (CD44v6) is a splice variant of the CD44 gene, a cell-surface glycoprotein that serves as the primary receptor for hyaluronan (UniProt P16070). The inclusion of the v6 exon in the mRNA transcript confers unique functional properties to the protein, specifically allowing it to act as an essential co-receptor for receptor tyrosine kinases such as c-Met and VEGFR-2, which triggers downstream signaling for cell survival and migration (Orian-Rousseau et al., 2002, PMID: 12488377). CD44v6 is highly overexpressed in various malignancies, including squamous cell carcinomas, colorectal cancer, and multiple myeloma, where it is strongly associated with metastatic potential and poor prognosis (Heider et al., 2004, PMID: 15507674). While CD44v6 has been a primary target for monoclonal antibodies and antibody-drug conjugates (ADCs) like bivatuzumab mertansine, clinical development was historically hindered by severe on-target, off-tumor skin toxicities, such as Toxic Epidermal Necrolysis, due to CD44v6 expression in normal squamous epithelium (Sauter et al., 2007, PMID: 17664469). Modern therapeutic strategies have shifted toward CD44v6-directed CAR-T cell therapies and RNA-based interference (siRNA) to specifically silence CD44v6 mRNA, aiming to inhibit tumor invasion while managing safety through controlled expression or suicide switches (Casucci et al., 2013, PMID: 23861244; NCT04427449).

Other names

CD44 exon v6CD44R1pIIICD44v6 transcriptEpicanHeparan sulfate proteoglycan

Targeting of the v6-encoded epitope to deliver cytotoxic payloads via antibody-drug conjugates, induction of T-cell mediated lysis via CAR-T cells, or silencing of the CD44v6 mRNA transcript via RNA interference to disrupt c-Met/VEGFR-2 signaling.