Understanding the Unique Attributes of MUC16 (CA125): Potential Implications in Targeted Therapy

Abstract

CA125, the most widely used ovarian cancer (OC) biomarker, was first identified approximately thirty-five years ago in an antibody screen against OC antigen. Two decades later, it was cloned and characterized to be a transmembrane mucin, MUC16. Since then several studies have investigated its expression, functional and mechanistic involvement in multiple cancer types. Antibody based therapeutic approaches primarily using antibodies against the tandem repeat domains of MUC16 (for example Oregovomab and Abagovomab) have been the modus operandi for MUC16 targeted therapy, but met with very limited success. In addition, efforts are also made to disrupt the functional co-operation of MUC16 and its interacting partners, for example use of a novel immunoadhesin HN125 to interfere MUC16 binding to mesothelin. Since the identification of CA125 to be MUC16, it is hypothesized to undergo proteolytic cleavage, a process that is considered to be critical in determining the kinetics of MUC16 shedding as well as generation of a cell associated carboxyl-terminal fragment with potential oncogenic functions. In addition to our experimental demonstration of MUC16 cleavage, recent studies have demonstrated the functional importance of carboxyl terminal fragments of MUC16 in multiple tumor types. Here, we provide how our understanding of the basic biological processes involving MUC16 influences our approach towards MUC16 targeted therapy.

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma

“…MUC16 is believed to play important roles not only in normal contexts such as reproduction and proliferation, but also in pathologic states including cancer and mucosal infections. It exerts its function in cancer by many mechanisms such as migration, invasion, cell cycle control and metabolism reprogramming (16,17). Since its discovery, CA125 is usually used as a tumor marker, and many efforts have been given to its contribution to tumor malignancies, yet little is known about its regulation.…”

Targeting MUC16 in Cancer Therapy

“…MUC16 also binds to mesothelin, a protein involved in peritoneal metastases of ovarian cancers. Other properties include inhibition of apoptosis, contributing to chemotherapy resistance [8,11,18] and activation of STAT3 through JAK2, which increases cell proliferation [3,13]. Additionally, MUC16 is implicated in reducing the immune system response by binding to inhibitory receptors on natural killer (NK) cells [1,19] and decreasing expression of CD16, a cytokine that stimulates NK cells [20,21].…”

“…There have been a number of antibodies developed against CA125, an epitope of MUC16 contained in the tandem repeat region, for the treatment of ovarian cancer as a potential front line therapy, and a maintenance drug to prevent recurrence disease [8]. Mab-B43.13, also called oregovomab, is a monoclonal antibody that binds to CA125 forming antigen-antibody complexes to stimulate an immune response [40,41].…”

“…This may be due to the fact that the extracellular domain of MUC16 undergoes cleavage, which reduces the binding of these monoclonal antibodies to the tumour cells. Furthermore, due to the shedding of MUC16, it is also likely that the drug binds to circulating MUC16 in the serum, hence only a small fraction ever reaches the tumour cells [8]. Therefore, to improve current immunotherapy for MUC16, it would be necessary to generate antibodies against the carboxyl terminal domain that does not undergo cleavage.…”

“…Several hundred oligosaccharides are attached to the N-terminal domain through O-linked glycosylation and N-linked glycosylation whilst the tandem repeat region (TRR) has approximately 60 repeats of a 156 amino acid sequence, with disulphide bonds that confers structural stability. Attached to the TRR is a smaller C-terminal domain that also contains a cytoplasmic tail involved in intracellular cell events ( Figure 1) [1,3,8].…”