Su J.-C.Mar A.-C.Wu S.-H.Tai W.-T.Chu P.-Y.Wu C.-Y.Tseng L.-M.Lee T.-C.Chen K.-F.Liu C.-Y.HAO-CHIEH CHIUShiau C.-W.2021-06-242021-06-2420162045-2322https://scholars.lib.ntu.edu.tw/handle/123456789/566128Patients with triple-negative breast cancer (TNBC) had an increased likelihood of distant recurrence and death, as compared with those with non-TNBC subtype. Regorafenib is a multi-receptor tyrosine kinase (RTK) inhibitor targeting oncogenesis and has been approved for metastatic colorectal cancer and advanced gastrointestinal stromal tumor. Recent studies suggest regorafenib acts as a SHP-1 phosphatase agonist. Here, we investigated the potential of regorafenib to suppress metastasis of TNBC cells through targeting SHP-1/p-STAT3/VEGF-A axis. We found a significant correlation between cancer cell migration and SHP-1/p-STAT3/VEGF-A expression in human TNBC cells. Clinically, high VEGF-A expression is associated with worse disease-free and distant metastasis-free survival. Regorafenib induced significant anti-migratory effects, in association with downregulation of p-STAT3 and VEGF-A. To exclude the role of RTK inhibition in regorafenib-induced anti-metastasis, we synthesized a regorafenib derivative, SC-78, that had minimal effect on VEGFR2 and PDGFR kinase inhibition, while having more potent effects on SHP-1 activation. SC-78 demonstrated superior in vitro and in vivo anti-migration to regorafenib. Furthermore, VEGF-A dependent autocrine/paracrine loops were disrupted by regorafenib and SC-78. This study implies that SHP-1/p-STAT3/VEGF-A axis is a potential therapeutic target for metastatic TNBC, and the more potent SC-78 may be a promising lead for suppressing metastasis of TNBC.[SDGs]SDG3carbanilamide derivative; protein tyrosine phosphatase SHP 1; PTPN6 protein, human; pyridine derivative; regorafenib; STAT3 protein; vasculotropin A; animal; autocrine effect; cell motion; drug effect; drug screening; female; genetics; human; Kaplan Meier method; metabolism; metastasis; nude mouse; paracrine signaling; triple negative breast cancer; tumor cell line; Animals; Autocrine Communication; Cell Line, Tumor; Cell Movement; Female; Humans; Kaplan-Meier Estimate; Mice, Nude; Neoplasm Metastasis; Paracrine Communication; Phenylurea Compounds; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Pyridines; STAT3 Transcription Factor; Triple Negative Breast Neoplasms; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assaysjournal article10.1038/srep28888273649752-s2.0-84976891167