CDH6, also known as fetal kidney cadherin or K-cadherin, is involved in the morphogenesis and development of the embryonic kidney, driving the mesenchymal-epithelial differentiation necessary for renal morphogenesis. It plays an important role in the targeted treatment of ovarian cancer.
Expression distribution of CDH6
CDH6 is primarily expressed in specialized epithelial cells, neurons, glial cells, muscle cells, glandular epithelial cells, and proximal renal tubular cells. CDH6 is highly expressed in advanced ovarian and renal cancers.
(Data source: Uniprot)
Structure of CDH6
CDH6 is a type I transmembrane protein composed of 790 amino acids. It is characterized by five EC domains and a large cytoplasmic domain that interacts with beta-catenin molecules. CDH6 contains an RGD motif in the EC1 domain, which mediates binding to the αIIbβ3 integrin. The EC5 domain contains a His-Ala-Val (HAV) motif that stabilizes and aggregates adjacent monomers.
(Data source: AlphaFold)
CDH6 signaling pathway and regulation:
In cells with high αIIbβ3 expression, CDH6 binds to αIIbβ3, leading to activation of the α2β1 integrin, which in turn activates signaling pathways such as Src, FAK (focal adhesion kinase), AKT, and ERK (extracellular signal-regulated kinase). These signaling pathways play a key role in cell proliferation, migration, invasion, and survival. In cells with low αIIbβ3 expression, CDH6 and CDH17 bind to the α2β1 integrin, activating signaling pathways that promote cell adhesion, proliferation, migration, and invasion.
(Data from Bartolomé RA, Robles J, Martin-Regalado Á, et al. Mol Oncol. 2021)
Targeted therapy for CDH6
Raludotatug deruxtecan (R-DXd) is a CDH6-targeting ADC conjugated to a topoisomerase inhibitor for the treatment of fallopian tube cancer, platinum-resistant fallopian tube cancer, and platinum-resistant ovarian cancer. In a Phase I trial, 42 patients who had extensive prior PROC therapy demonstrated an ORR of 38%, a median DOR of 18.5 weeks, and a 50% rate of treatment-emergent adverse events in Cohort 3. The drug is currently being evaluated in the Phase 2/3 REJOICE-Ovairan01 trial, with the first patient dosed in China on August 6, 2024.
(Data source: Daiichi Sankyo official website)
