Targeting Shp-1 Mediated Vegf Signaling To Block The Migration Of Human Triple Negative Breast Cancer

Patients 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. Recently, scientists have suggested that regorafenib also acts as a SHP-1 phosphatase agonist. In this study, we aimed to investigate the role of regorafenib in suppressing metastasis of TNBC cells through targeting the SHP-1/p-STAT3/VEGF-A axis. We first observed a significant correlation between migration ability and SHP-1/p-STAT3/VEGF-A expression in several human TNBC cell lines. Importantly, we also demonstrated that VEGF-A expression is correlated with worse disease-free and distant metastasis-free survival in clinical TNBC patients. Furthermore, we showed that regorafenib could inhibit the migration of human TNBC cells, which was related to 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. This study indicated that the SHP-1/p-STAT3/VEGF-A axis is a potential therapeutic target for metastatic TNBC, and SC-78 may be a promising lead compound for suppressing metastasis of TNBC. (Grant supported by MOST 104-2628-B-075-001-MY3, MOST 105-2325-B-010-007, 105F026 ) Citation Format: Jung-Chen Su, Ai-Chung Mar, Chun-Yu Liu, Kuen-Feng Chen, Chung-Wai Shiau. Targeting SHP-1 mediated VEGF signaling to block the migration of human triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2074. doi:10.1158/1538-7445.AM2017-2074