Abstract Patients with metastatic triple-negative breast cancer (TNBC) relapse quickly, representing an unmet need for effective therapy. Regorafenib is a multi-receptor tyrosine kinase (RTK) inhibitor targeting tumor angiogenesis, oncogenesis and the tumor microenvironment and has been approved for metastatic colorectal cancer and advanced gastrointestinal stromal tumor. Recent studies suggest regorafenib also acts as a SHP-1 phosphatase agonist. Here, we investigated the potential of regorafenib to suppress metastasis of TNBC cells by mitigating autocrine and paracrine feed-forward loops of p-STAT3-mediated VEGF-A signaling through targeting the SHP-1/p-STAT3/VEGF axis. We found a significant correlation between cancer cell migration and SHP-1/p-STAT3/VEGF-A expression in a panel of human TNBC cells. Clinically VEGF-A expression is associated with disease-free and distant metastasis-free survival, independent of tumor stage. Regorafenib induced significant anti-migratory effects, in association with downregulation of p-STAT3 and VEGF-A. Overexpression and knockdown experiments validated the indispensable roles of SHP-1, p-STAT3 and VEGF-A in regorafenib-induced anti-migration. To exclude the role of RTK inhibition in regorafenib-induced inhibition of migration, 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/p-STAT3/VEGF-A signaling. SC-78 demonstrated superior in vitro anti-migration to regorafenib. Furthermore, VEGF-A dependent autocrine/paracrine loops were disrupted by regorafenib and SC-78. SC-78 revealed more potent in vivo efficacy than regorafenib in both xenograft and orthotopic models, as well as in a tail vein metastatic model. This study implies that the more potent SC-78 may be a promising lead for suppressing metastasis of TNBC, and the SHP-1/p-STAT3/VEGF axis is a potential therapeutic target for metastatic TNBC. Citation Format: Jung-Chen Su, Hao-Chieh Chiu, Chun-Yu Liu, Kuen-Feng Chen, Chung-Wai Shiau. Disrupting p-STAT3-mediated VEGF-A paracrine and autocrine feed-forward loops by targeting SHP-1 suppresses triple negative breast cancer cell metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3825.