DCZ0415, a small‐molecule inhibitor targeting TRIP13, inhibits EMT and metastasis via inactivation of the FGFR4/STAT3 axis and the Wnt/β‐catenin pathway in colorectal cancer

STAT3 Transcription Factor 0301 basic medicine Epithelial-Mesenchymal Transition TRIP13 colorectal cancer Cell Cycle Proteins Mice 03 medical and health sciences Cell Line, Tumor granzyme B metastasis Animals Humans Receptor, Fibroblast Growth Factor, Type 4 Wnt Signaling Pathway RC254-282 Research Articles beta Catenin Cell Proliferation DCZ0415 NF-kappa B Neoplasms. Tumors. Oncology. Including cancer and carcinogens 3. Good health Gene Expression Regulation, Neoplastic FGFR4 ATPases Associated with Diverse Cellular Activities Colorectal Neoplasms
DOI: 10.1002/1878-0261.13201 Publication Date: 2022-02-23T08:54:52Z
ABSTRACT
Thyroid receptor‐interacting protein 13 (TRIP13), a of the AAA‐ATPase family, is upregulated in various human cancers, including colorectal cancer (CRC). This study focused on inhibition TRIP13‐induced CRC progression and signalling by DCZ0415, small molecule targeting TRIP13. It demonstrated potent antitumour activity TRIP13‐deregulated cell lines, regardless their p53, KRAS, BRAF, epidermal growth factor receptor or microsatellite instability status. The treatment cells with DCZ0415 resulted decreased proliferation, induced cycle arrest G2‐M phase increased apoptosis. diminished xenograft tumour metastasis immunocompromised mice. reduced expression fibroblast 4 (FGFR4), signal transducer activator transcription 3 (STAT3), proteins associated epithelial‐mesenchymal transition nuclear kappa B (NF‐κB) pathways xenografts exhibiting high Additionally, cyclin D1, β‐catenin T‐cell 1, leading to inactivation Wnt/β‐catenin pathway. In syngeneic model, an immune response decreasing PD1 CTLA4 levels increasing granzyme B, perforin interferon gamma. sum, DCZ04145 inhibits TRIP13–FGFR4–STAT3 axis, inactivates NF‐κB signalling, activates reduces CRC. provides rationale evaluate clinically for subset CRCs that exhibit dysregulated TRIP13 FGFR4.
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