2,4-Diamino-Quinazoline, a Wnt Signaling Inhibitor, Suppresses Gastric Cancer Progression and Metastasis

• Published in: International journal of molecular sciences 2020-08, Vol.21 (16), p.5901
• Main Authors: Chang, Te-Sheng, Lu, Chung-Kuang, Hsieh, Yung-Yu, Wei, Kuo-Liang, Chen, Wei-Ming, Tung, Sui-Yi, Wu, Cheng-Shyong, Chan, Michael W Y, Chiang, Ming-Ko
• Format: Article
• Language: English
• Subjects: Aged; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Axin Protein - genetics; Axin Protein - metabolism; Cell adhesion & migration; Cell Line; Cell Line, Tumor; Cells, Cultured; Clinical trials; Female; Gastric cancer; Gene expression; Genes; Humans; Inhibitors; Lymphoid Enhancer-Binding Factor 1 - antagonists & inhibitors; Lymphoid Enhancer-Binding Factor 1 - genetics; Lymphoid Enhancer-Binding Factor 1 - metabolism; Male; Metastases; Mice; Mice, Nude; Middle Aged; Myc protein; Neoplasm Metastasis; Organoids; Patients; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Quinazolines - pharmacology; Quinazolines - therapeutic use; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Sequence analysis; Signal transduction; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Tumorigenesis; Tumors; Wnt protein; Wnt Signaling Pathway - drug effects; Xenografts; Xenotransplantation; β-Catenin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21165901

Gastric cancer (GC) is among the most treatment-refractory epithelial malignancies. Aberrant activation of Wnt/β-catenin-signaling has been implicated in a variety of human cancers, including gastric cancer. Here we report that the elevated expression of lymphoid enhancer binding factor 1 (Lef1) is associated with the TNM (tumor- node-metastasis) stage of gastric cancer. Subsequently, 2,4-diamino-quinazoline (2,4-DAQ), a selective inhibitor of Lef1, was identified to suppress the expression of Wnt/β-catenin target genes such as AXIN2, MYC and LGR5 and result in the suppression of gastric cancer cell growth through the apoptotic pathway. The 2,4-DAQ also exhibited an inhibitory effect on the migration/invasion of gastric cancer cells. Importantly, the treatment of human gastric tumor xenograft with 2,4-DAQ suppressed tumor growth in a nude mouse model. Furthermore, 2,4-DAQ appears effective on patient-derived organoids (PDOs). Transcriptome sequencing analysis also revealed that 2,4-DAQ are more effective on the gastric cancers that exhibit higher expression levels of Wnt-signaling pathway-related genes than their adjacent normal gastric tissues.