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

Abstract

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 cancers of the alimentary tract and metastasis. The DOG1 expression profile was determined among TCGA samples and tissue microarrays. High levels of DOG1 expression were ubiquitously observed in multiple cancer samples from the alimentary tract 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 via 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 in vitro. 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.

The role of anoctamin 1 in liver disease

“… 32 In addition, ANO1 is highly expressed in HCC, and when it is knocked down, ANO1 regulates the cell cycle and inhibits cell proliferation and metastasis through the MAPK signalling pathway 33 ; however, the mechanism of action of ANO1 overexpression in HCC is still unclear and needs to be further investigated in the future. ANO1 is also involved in secondary liver metastasis of CRC 127 and may be a potential therapeutic target. However, whether ANO1 is also involved in other secondary metastases of tumours needs further study.…”

“…[123][124][125] ANO1 is highly expressed in CRC, especially in liver metastases. 126 To explore the role of ANO1 in CRC liver metastasis, Wu et al 127 found that when bioluminescence was imaged in the livers of mice treated with an anti-ANO1 antibody by establishing an anti-ANO1…”

“…ANO1 is highly expressed in CRC, especially in liver metastases 126 . To explore the role of ANO1 in CRC liver metastasis, Wu et al 127 . found that when bioluminescence was imaged in the livers of mice treated with an anti‐ANO1 antibody by establishing an anti‐ANO1 antibody‐treated mouse model of CRC liver metastasis, only a few tumour nodules were observed by the naked eye when low concentrations of the anti‐ANO1 antibody were used, and virtually no tumour nodules were observed when high concentrations were used, while both concentrations reduced the serum ALT, AST and total bilirubin.…”

Drug conjugates for the treatment of lung cancer: from drug discovery to clinical practice

“…DM1 maytansinoid derivatives (emtansine and mertansine) are potent drugs with broad lethal effects on xenografts of non-Hodgkin's lymphoma in vivo [106]. DM4 drugs include soravtansine and ravtansine, which can enhance the "bystander effect" of adjacent cells in vivo, thereby eradicating tumors [107]. Effective payloads that act by damaging DNA include calicheamicin, doxorubicin, and camptothecin-like drugs.…”