Abstract B17: Activating AMPK signaling by SCT-1015 to suppress tumor growth on triple negative breast cancer cells

Abstract

Abstract AMPK (AMP-activated protein kinase) is one of the central regulators of cellular and organismal metabolism that has been linked to the regulation of tumor progression; however, its biologic functions and signaling cascades remain unclear. Recently, many AMPK activators, including metformin, phenformin, and nilotinib, have shown anticancer efficacy. Nilotinib is a small-molecule tyrosine kinase inhibitor approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML). In our previous study, we found that nilotinib increased AMPK phosphorylation and led to autophagic cell death in human hepatocellular carcinoma (HCC) cells. To dissect the involvement of Bcr-Abl kinases in nilotinib-mediated cell death in human TNBC cells, we designed a series of new compounds, with structure similar to nilotinib but without hinge-binding activity in the ATP binding pocket of kinases. In this work, we found one of the nilotinib analogues, SCT-1015, showed better efficacy on AMPK activation and cell death induction compared to nilotinib without inhibiting Bcr-Abl kinase in human TNBC cells. Moreover, we demonstrate that SCT-1015 increased AMPK phosphorylation and inhibited cell proliferation in TNBC. Importantly, SCT-1015 suppressed tumor growth in HCC1806 orthotopic mice model. Our study indicates that targeting AMPK signaling pathway may be a useful approach for the development of targeted agents for anti-breast cancer. Citation Format: Jung-Chen Su, Jui-Wen Huang, Chung-Wai Shiau. Activating AMPK signaling by SCT-1015 to suppress tumor growth on triple negative breast cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B17.