Mucin-1: a promising pan-cancer therapeutic target

Abstract

Mucin1 or MUC1 (also known as CD227, EMA, MCD, MAM6, PEM, PUM, KL-6, CA 27.29/CA 15-3) is a highly glycosylated transmembrane mucin family member protein that is overexpressed in various solid or hematological cancers. Abnormal MUC1 expression/glycosylation in cancer leads to the activation of multiple pathways, resulting in tumor migration, invasion and accelerated growth. CA 27.29/CA 15-3 are blood tumor markers used in breast cancer patients. Novel therapeutic agents targeting MUC1, including cancer vaccines, cellular therapies, radiopharmaceuticals, monoclonal antibodies and antibody-drug conjugates, are being explored in clinical studies. The current review summarizes the molecular mechanisms of MUC1 in cancer and highlights existing data for MUC1-targeting agents in the therapeutic pipeline.

Fig. 1. MUC1 expression across selected cancer types.

MUC1 is commonly overexpressed in epithelial cancers. Overexpression per immunohistochemistry may be found in as many as 86% of lung adenocarcinomas, 94% of triple-negative breast cancers, 100% of ovarian cancers, 60% of cervical cancers and 86% of endometrial cancers. Among gastrointestinal cancers, MUC1 is significantly expressed in cholangiocarcinoma (65%), pancreatic (60%), hepatocellular (70%) and colorectal cancers (55%). MUC1 is also significantly expressed in genitourinary malignancies such as urothelial carcinoma (62%). MUC1 is also overexpressed in hematological malignancies such as cutaneous T-cell lymphoma (50%) as assessed by competitive chemiluminescence^–.

Fig. 2. Graphical representation of molecular mechanisms of MUC1 in cancer.

MUC1 overexpression results in the activation of JNK, which drives TGF-ß to switch its role from tumor-suppressor to tumor promoter (stimulating increased tumor cell viability) and may also activate the Wnt/β-catenin pathway, resulting in tumor progression and metastases. Disruption of tumor apoptosis and inhibition of T-cell proliferation are yet other mechanisms driving cancer progression and immunosuppression. MUC1 overexpression also upregulates the PI3K/AKT pathway, which is crucial for the regulation of cell cycle, survival and metabolism of cancer. MUC1 overexpression may also directly activate the NF-κB p65 transcription factor, thereby blocking cell death and promoting tumor cell growth. MUC1 can also lead to metabolic alterations, which may facilitate cancer cell survival. By induction of PD-L1, MUC1 may also contribute to cancer cell immune evasion. Akt protein kinase B, EGFR epidermal growth factor receptor, JNK c-Jun N-terminal kinase, MAPK mitogen-activated protein kinase, PI3K phosphatidylinositol 3-kinase, PD-L1 programmed death-ligand 1TA-MUC1 tumor-associated MUC1. TGF-β transforming growth factor- β, VEGF vascular endothelial growth factor.

Fig. 3. The landscape of MUC1-based therapeutic agents.

Several novel therapeutic agents targeting MUC1 have demonstrated promising activity in pre-clinical studies and early-phase clinical trials and are also being tested in ongoing clinical trials, including cellular therapies, vaccines, radiopharmaceuticals, monoclonal antibodies and antibody-drug conjugates. CAR chimeric antigen receptor.