Abstract 4179: A novel approach for antimetastatic therapies against TNBC utilizing a physiologic suppressor

Abstract

Abstract Metastatic progression of tumors is the major cause of death in patients with triple-negative breast cancer (TNBC). However, since metastasis is a multistep process, unraveling its complexity is a major challenge. One effective way of tackling this question is to study natural blockers of the metastatic process, metastasis suppressors, and identify the mechanisms by which they regulate metastasis. Raf kinase inhibitory protein (RKIP), a protein that regulates kinase activity, is a suppressor of TNBC metastasis. Although RKIP inhibits the activity of key kinases such as Raf-1, GRK2, NIK/IKK in cultured cells, the kinase targets of RKIP in tumors are not known. To address this question, we used a mass spectrometry approach involving inhibitor-conjugated beads to identify kinases that are downregulated by RKIP in human TNBC xenograft tumors. Our results identified a network of stress kinases targeted by RKIP, including kinases that have not been previously reported as RKIP targets. In order to unravel the effect of this stress network on metastatic gene expression, we investigated genes that correlate with RKIP expression in TCGA breast cancer patient data set. We identified prometastatic genes such as APC and DOCK4 as novel RKIP targets in in vitro and in vivo models of TNBC. We also demonstrated these genes are downstream of the RKIP-stress network. Finally, by using a high-throughput invasion assay, we developed a low-dose multidrug cocktail of small-molecule kinase inhibitors that mimic RKIP's antimetastatic role in TNBCs. Elucidating RKIP function at a systems level reveals the interplay between key metastatic signaling cascades, particularly in relation to cell motility and invasion. Our findings suggest that the low-dose multidrug combination that targets a network of stress kinases is a viable antimetastatic therapy for TNBC patients. Citation Format: Ali Ekrem Yesilkanal, Daniel C. Rabe, Payal Tiwari, Casey Frankenberger, Gary L. Johnson, Marsha Rosner. A novel approach for antimetastatic therapies against TNBC utilizing a physiologic suppressor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4179.