Abstract 441: Targeting MKK3-MYC complex to reduce racial survival disparity in breast cancer

Abstract

Abstract Breast cancer is the most common cancer and the leading cause of cancer-related death in women. The triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. African American women experience up to 2-fold higher incidence of TNBC as compared to White women. Moreover, African Americans die from breast cancer at up to 40% higher rate than White and Hispanic women. However, there is no therapeutic options are currently available to reduce survival disparity in breast cancer. To address this unmet medical need, we develop novel computational methods combined with experimental chemical biology and high-throughput screening (HTS) technologies. Using our specially designed bioinformatics workflow, we discovered that high expression of mitogen-activated protein kinase kinase 3 (MKK3) strongly correlates with worsened clinical outcomes in African American TNBC patients. The analysis of TNBC patient genomic profiles revealed that MKK3 promotes TNBC in part by activating the major tumor driver transcription factor MYC. MYC is a highly appealing therapeutic target in TNBC, however, no approved MYC inhibitors are available. We found that MKK3 binds and activates MYC through protein-protein interaction (PPI) in TNBC cells. Both genetic and pharmacological inhibition of the MKK3/MYC complex suppresses MYC activity and the viability of TNBC cells. Thus, MKK3/MYC interaction represents a novel vulnerability for therapeutic intervention in TNBC. By combining computational modeling with experimental HTS, we have discovered the first small molecule MKK3/MYC PPI inhibitors. For example, a quinoline derivative SGI-1027 disrupts the MKK3/MYC complex in cells and in vitro, inhibits MYC transcriptional activity, and suppresses the viability of TNBC cells. Together, our studies revealed a novel mechanism of TNBC tumorigenesis through MKK3-induced MYC activation, establish a new HTS to enable the discovery of potent and selective inhibitors to regulate MKK3/MYC complex, and may open new clinical strategies to reduce racial disparity in TNBC mortality. Acknowledgments: This work was supported in part by Mary Kay Ash Foundation Grant for Cancer Research (A.A.I.), Emory initiative on Biological Discovery through Chemical Innovation (A.A.I.), NCI’s Informatics Technology for Cancer Research (ITCR) Program (R21CA274620, A.A.I.), NCI Cancer Target Discovery and Development (CTD^2) Network (U01CA217875, H.F.), NCI Emory Lung Cancer SPORE (P50CA217691, H.F.), Career Enhancement Program (A.A.I., P50CA217691), Winship Cancer Institute (NIH 5P30CA138292).