GUCY2C

Official Full Name

guanylate cyclase 2C

Organism

Homo sapiens

GeneID

2984

Background

This gene encodes a transmembrane protein that functions as a receptor for endogenous peptides guanylin and uroguanylin, and the heat-stable E. coli enterotoxin. The encoded protein activates the cystic fibrosis transmembrane conductance regulator. Mutations in this gene are associated with familial diarrhea (autosomal dominant) and meconium ileus (autosomal recessive). [provided by RefSeq, Nov 2016]

Synonyms

GCC; GC-C; HSER; STAR; DIAR6; GUC2C; MECIL; MUCIL;

Bio Chemical Class

Phosphorus-oxygen lyase

Protein Sequence

MKTLLLDLALWSLLFQPGWLSFSSQVSQNCHNGSYEISVLMMGNSAFAEPLKNLEDAVNEGLEIVRGRLQNAGLNVTVNATFMYSDGLIHNSGDCRSSTCEGLDLLRKISNAQRMGCVLIGPSCTYSTFQMYLDTELSYPMISAGSFGLSCDYKETLTRLMSPARKLMYFLVNFWKTNDLPFKTYSWSTSYVYKNGTETEDCFWYLNALEASVSYFSHELGFKVVLRQDKEFQDILMDHNRKSNVIIMCGGPEFLYKLKGDRAVAEDIVIILVDLFNDQYFEDNVTAPDYMKNVLVLTLSPGNSLLNSSFSRNLSPTKRDFALAYLNGILLFGHMLKIFLENGENITTPKFAHAFRNLTFEGYDGPVTLDDWGDVDSTMVLLYTSVDTKKYKVLLTYDTHVNKTYPVDMSPTFTWKNSKLPNDITGRGPQILMIAVFTLTGAVVLLLLVALLMLRKYRKDYELRQKKWSHIPPENIFPLETNETNHVSLKIDDDKRRDTIQRLRQCKYDKKRVILKDLKHNDGNFTEKQKIELNKLLQIDYYNLTKFYGTVKLDTMIFGVIEYCERGSLREVLNDTISYPDGTFMDWEFKISVLYDIAKGMSYLHSSKTEVHGRLKSTNCVVDSRMVVKITDFGCNSILPPKKDLWTAPEHLRQANISQKGDVYSYGIIAQEIILRKETFYTLSCRDRNEKIFRVENSNGMKPFRPDLFLETAEEKELEVYLLVKNCWEEDPEKRPDFKKIETTLAKIFGLFHDQKNESYMDTLIRRLQLYSRNLEHLVEERTQLYKAERDRADRLNFMLLPRLVVKSLKEKGFVEPELYEEVTIYFSDIVGFTTICKYSTPMEVVDMLNDIYKSFDHIVDHHDVYKVETIGDAYMVASGLPKRNGNRHAIDIAKMALEILSFMGTFELEHLPGLPIWIRIGVHSGPCAAGVVGIKMPRYCLFGDTVNTASRMESTGLPLRIHVSGSTIAILKRTECQFLYEVRGETYLKGRGNETTYWLTGMKDQKFNLPTPPTVENQQRLQAEFSDMIANSLQKRQAAGIRSQKPRRVASYKKGTLEYLQLNTTDKESTYF

Open

Disease

Chronic pancreatitis, Crohn disease, Irritable bowel syndrome, Malignant digestive organ neoplasm, Solid tumour/cancer, Ulcerative colitis

Approved Drug

3 +

Clinical Trial Drug

3 +

Discontinued Drug

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Detailed Information

GUCY2C (Guanylate Cyclase C) represents a significant therapeutic target in cancer treatment, particularly for colorectal cancer. This transmembrane receptor, primarily expressed on the luminal surface of intestinal epithelial cells, plays a crucial role in maintaining intestinal homeostasis through its interaction with endogenous ligands guanylin and uroguanylin. When these ligands bind to GUCY2C, they trigger the conversion of GTP to cGMP, initiating downstream signaling pathways that regulate fluid and electrolyte balance while maintaining intestinal barrier integrity.

Figure 1 illustrates the GUCY2C-cGMP signaling axis and its role in intestinal fluid secretion, showing how activation of the GUCY2C receptor by its ligands increases intracellular cGMP levels. Figure 1. GUCY2C-cGMP signaling axis. (Rappaport JA, et al., 2019)

Researchers and medication developers have taken great notice of GUCY2C's expression pattern in cancer tissues. Comprehensive research using 627 gastrointestinal tumor samples found that GUCY2C is very particular to colorectal cancer, with 98% of original tumors and 81% of metastatic lesions exhibiting positive membrane staining. When compared to non-colorectal cancers, which show only 8-15% membrane positive, this selectivity is very remarkable. The expression level of GUCY2C varies with tumor differentiation status; well-differentiated tumors usually have greater expression levels with specific apical surface localization, whereas poorly differentiated tumors show a more diffuse cytoplasmic staining pattern.

With differing degrees of effectiveness, many therapy strategies aimed at GUCY2C have surfaced. Preclinical research has shown great potential for Pfizer's PF-07062119, a bispecific antibody aimed against GUCY2C and CD3ε. At dosages as low as 0.3 mpk, the medication produced total tumor regression in many models including NSG mice trials with adoptively transplanted T cells. With very little to moderate gastrointestinal symptoms seen, the drug showed good safety profiles in cynomolgus monkeys. Pfizer stopped working on it in January 2024, however, citing strategic considerations rather than safety issues in light of these positive outcomes.

Another remarkable effort was Takeda's Indusatumab vedotin (TAK-264), an antibody-drug combination mixing the MMAE payload with a human anti-GCC antibody. Although early research indicated hope, clinical trials for pancreatic and stomach tumors revealed minimal effectiveness of the medication. Interestingly, the drug's efficacy seems to be affected not only by GUCY2C expression levels but also by its distribution pattern within tumor cells. Though the initiative was finally shut down in 2015, this finding sparked a significant new understanding of the link between target expression patterns and treatment results.

Recent breakthroughs that seem most promising have emerged from CAR-T cell treatments aimed at GUCY2C. In extensively pretreated MSS/pMMR metastatic colorectal cancer patients, GUCY2C-directed CAR-T treatment IM96 has shown promising outcomes. In clinical studies, it had a 26.3% total response rate; especially remarkable outcomes were seen in those with more GUCY2C expression. With a median progression-free survival of 7 months, the high-dose group showed an even superior response rate of 38.5%. Developed utilizing CoupledCAR technology, GCC19CART has also shown notable potential with a 40% partial response rate in advanced colorectal cancer patients. This treatment may provide better therapeutic effectiveness by specifically combining GCC-targeting features with CD19 CAR-T cell activation.

Particularly for colorectal cancer, these advances in GUCY2C-targeted medicines mark a major improvement in cancer therapy. Although cell-based treatments have so far shown the most encouraging outcomes, the sector is always changing. The varied efficacy of many treatment strategies underlines the need to know not only the existence of GUCY2C expression but also its pattern and location within cancer cells. Looking forward, there is still a great possibility for innovative methods—including T-cell engagers and next-generation ADCs—to provide more easily available and efficient therapy choices. The main difficulty is in maximizing patient selection according to GUCY2C expression patterns and creating more affordable therapy options that might serve a larger patient group.

The GUCY2C-targeted therapy development scene reflects the possibilities and difficulties in contemporary cancer treatment creation. Although some methods have struggled, the general trend indicates that GUCY2C is still a useful target, especially for challenging-to-treat diseases like metastatic colorectal cancer. Therapeutic strategy development and improved knowledge of target expression patterns help to indicate more and more successful future therapies.

References:

Rappaport JA, Waldman SA. The Guanylate Cyclase C-cGMP Signaling Axis Opposes Intestinal Epithelial Injury and Neoplasia. Front Oncol. 2018;8:299.
Entezari AA, Snook AE, Waldman SA. Guanylyl cyclase 2C (GUCY2C) in gastrointestinal cancers: recent innovations and therapeutic potential. Expert Opin Ther Targets. 2021;25(5):335-346.
Gong JP, Schulz S, Hyslop T, et al. GUCY2C molecular staging personalizes colorectal cancer patient management. Biomark Med. 2012;6(3):339-348.

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