Mucin-16 C-terminal domain (MUC16CD)

Mucin-16 C-terminal domain (MUC16CD) is the membrane-anchored portion of the Mucin-16 protein, a large transmembrane glycoprotein also known as CA-125 (UniProt Q8WXI7). While the N-terminal region of Mucin-16 is proteolytically cleaved and shed into the bloodstream as the clinical biomarker CA-125, the MUC16CD remains on the cell surface, consisting of a retained ectodomain, a transmembrane domain, and a short cytoplasmic tail (PMID: 39346763). This domain is highly overexpressed in several malignancies, most notably epithelial ovarian cancer and pancreatic ductal adenocarcinoma, where it promotes tumor progression by mediating cell-cell adhesion through interactions with mesothelin (PMID: 31466494). Additionally, the cytoplasmic tail of MUC16CD facilitates oncogenic signaling by activating pathways such as JAK2/STAT3 and Src, which enhance cell proliferation, survival, and chemoresistance (PMID: 22348514). Because it is not shed, MUC16CD is considered a superior therapeutic target compared to the full-length protein, as it avoids the decoy effect of circulating CA-125 that can sequester targeted therapies (PMID: 25512218). Current drug development efforts focusing on MUC16CD include chimeric antigen receptor (CAR) T cells like PRGN-3005, bispecific T-cell engagers like ubamatamab, and antibody-drug conjugates designed to selectively eliminate MUC16-positive tumor cells (ClinicalTrials.gov NCT03907527).

Other names

MUC16-CDMUC16-CTDMUC16-CMUC16-ectoCancer antigen 125CA-125

MUC16CD is targeted by immunotherapies such as CAR T cells and bispecific antibodies to redirect T-cell cytotoxicity against tumor cells, and by antibody-drug conjugates to deliver cytotoxic payloads directly to the cancer cell (PMID: 39346763, ClinicalTrials.gov NCT03907527).