AUTHOR=Wu Yangping , Li Wenting , Chen Xiangzheng , Wang Haichuan , Su Siyuan , Xu Ying , Deng Xiangbing , Yang Tinghan , Wei Mingtian , Li Li , Liu Yixin , Yang Jinliang , Li Weimin 

TITLE=DOG1 as a novel antibody-drug conjugate target for the treatment of multiple gastrointestinal tumors and liver metastasis

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1051506

DOI=10.3389/fimmu.2023.1051506

ISSN=1664-3224

ABSTRACT=<p>Discovered On Gastrointestinal stromal tumors protein 1 (DOG1), a major calcium-activated chloride channel, has been used as a common diagnostic marker for gastrointestinal stromal tumors. However, the therapeutic application of DOG1 was not well defined. Here, we aim to investigate its potential as a therapeutic target for an antibody-drug conjugate (ADC) in various <uri xlink:href="https://www.sciencedirect.com/science/article/pii/S0027510704001381" xmlns:xlink="http://www.w3.org/1999/xlink">cancers of the alimentary tract</uri> and metastasis. The DOG1 expression profile was determined among TCGA samples and tissue microarrays. High levels of DOG1 expression were ubiquitously observed in multiple <uri xlink:href="https://www.sciencedirect.com/science/article/pii/S0027510704001381" xmlns:xlink="http://www.w3.org/1999/xlink">cancer samples from the alimentary tract</uri> determined by TCGA samples and tissue microarrays. Circulating tumor cells isolated from metastatic colon cancer patients were also positive for DOG1 expression. The mechanisms of anti-DOG1 antibody were investigated by dual-luciferase reporter assay. The anti-DOG1 antibody could inhibit proliferation and metastasis <italic>via</italic> p53 signaling in limited cancer cell lines. The anti-DOG1 antibody was conjugated with a microtubule inhibitor DM4, to construct a new anti-DOG1-DM4-ADC to strengthen its activity. The anti-DOG1-DM4-ADC showed cytotoxicity at the nanomolar level <italic>in vitro.</italic> In the murine xenograft tumor models, treatment of anti-DOG1-DM4-ADC achieved a significant tumor growth inhibition rate. Our study indicates that anti-DOG1-DM4-ADC may be promising therapeutic molecules for DOG1-positive alimentary tract tumors and may be effective in inhibiting recurrence after curative resection of liver metastases of colorectal origin.</p>