Guanylyl cyclase C as a diagnostic and therapeutic target in colorectal cancer

Abstract

Colorectal cancer remains a major cause of mortality in the USA, despite advances in prevention and screening. Existing therapies focus primarily on generic treatment such as surgical intervention and chemotherapy, depending on disease severity. As personalized medicine and targeted molecular oncology continue to develop as promising treatment avenues, there has emerged a need for effective targets and biomarkers of colorectal cancer. The transmembrane receptor guanylyl cyclase C (GUCY2C) regulates intestinal homeostasis and has emerged as a tumor suppressor. Further, it is universally expressed in advanced metastatic colorectal tumors, as well as other cancer types that arise through intestinal metaplasia. In this context, GUCY2C satisfies many characteristics of a compelling target and biomarker for gastrointestinal malignancies.

Keywords: GUCY2C; biomarker; cancer prevention; colorectal cancer; guanylin; guanylyl cyclase C; hormone replacement; linaclotide; plecanatide; uroguanylin.

Figure 1.. Guanylyl cyclase C signaling cascade in the intestinal epithelium.

Epithelial cells along the intestinal tract express GUCY2C on their apical surface, where it is activated by its endogenous ligands guanylin and uroguanylin, or the super agonist enterotoxigenic peptide ST. Activation of GUCY2C produces intracellular cGMP, which, by activating PKGII, creates an electrolyte gradient via CFTR activation and NHE3 inactivation. This signaling cascade promotes fluid secretion into the intestinal lumen, as well as regulates critical cellular processes such as metabolic activity, barrier integrity and genomic stability.

Figure 2.. Frequency of colorectal cancer gene mutations.

Analysis of TCGA-COAD cohort indicates frequency of simple somatic mutations in five commonly mutated colorectal cancer genes, APC, TP53, KRAS, PIK3CA, SMAD4 as well as GUCY2C, GUCA2B, and GUCA2A. The total TCGA-COAD cohort assessed consists of n = 400 cases. The data were compiled directly from the TCGA Research Network: www.cancer.gov/tcga. TCGA-COAD: The Cancer Genome Atlas colorectal adenocarcinoma.

Figure 3.. GUCY2C-targeted therapies along the colorectal cancer disease continuum.

As a chemopreventative approach, ligand replacement by GUCY2C agonists could reconstitute cGMP signaling in the intestinal environment, restoring homeostasis and preventing hyperproliferation. Existing polyps may be removed surgically, and a GUCY2C-targeted vaccine can serve as a secondary preventative of recurring disease. In case of advanced or metastatic disease, T-cell therapy may be used as advanced treatment.