Abstract 4998: Targeting DHPS to abrogate TGFβ-induced metastasis in breast cancer

Progression of solid tumors to a metastatic stage accounts for over 90% of cancer mortality. Thus, it is critical to identify therapeutic strategies that target both primary and metastatic tumors. Epithelial-mesenchymal transition (EMT) negatively correlates with therapy response, contributing to intratumoral heterogeneity and systemic dissemination in breast cancer. We previously reported that pseudopodium-enriched atypical kinase one (PEAK1) promotes breast cancer cell EMT and metastasis by potentiating fibronectin-transforming growth factor beta (TGFβ) signaling cross-talk. Since eukaryotic initiation factor five A (eIF5A), a unique translation factor that is activated by deoxyhypusine synthase (DHPS)-dependent post-translational hypusination, is required for PEAK1 expression, we hypothesized that TGFβ may directly regulate eIF5A activity to promote EMT, and that targeted inhibition of this pathway may provide a novel means to inhibit or reverse metastatic progression. In this regard, we provide evidence of an active eIF5A-EMT program in undifferentiated breast cancer tissue. Notably, blockade of DHPS activity and eIF5A hypusination reduces PEAK1 translation, cell viability and TGFβ-induced EMT in vitro and metastasis in vivo. Conversely, we demonstrate that TGFβ induces post-translational hypusination of eIF5A in metastatic breast cancer cells. TGFβ is known to activate histone deacetylase six (HDAC6) and HDAC6 was independently reported to promote eIF5A deacetylation and nuclear export to support its translation functions. When delivered in combination, HDAC6 and DHPS inhibitors synergize to sequester eIF5A to the nucleus, suppress eIF5A-dependent translation and potently kill metastatic breast cancer cells. To identify candidate pathways downstream of the eIF5A/PEAK1 axis during EMT, we generated a Cytoscape interactome using eIF5A signaling and PEAK1-induced EMT genes as search terms. All interactome component genes were then analyzed across two breast cancer patient studies available on the Cancer BioPortal. Interestingly, SOX2, PIK3CA and EIF4A2 were the interactome nodes that exhibited copy number amplifications among patients harboring genomic alterations in the initial interactome search genes, and SOX2 amplification significantly and independently associated with decreased patient survival (p = 0.0476). Taken together, our results establish a novel node/axis by which TGFβ signaling stimulates HDAC6 and/or DHPS function to activate cytoplasmic eIF5A and promote EMT and survival of breast cancer cells within the metastatic niche, identifying new targeted therapy strategies that may improve cancer patient survival. Citation Format: Robert Guth, Lindsay Kutscher, Yvess Adamian, Cameron Geller, Kishan Bahkta, Kayla Meade, Jonathan A. Kelber. Targeting DHPS to abrogate TGFβ-induced metastasis in breast cancer [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 4998.