Abstract 2698: Phosphoproteomics-guided anticancer drug combination design with a novel small-molecule PP2A activator

Abstract

Abstract Significance: Phosphatases are cellular antagonists of kinase signaling and have a diverse range of substrates, many of which are ideal targets for small molecule-based anticancer treatment. Our lab and collaborators have generated a novel series of compounds that bind to and activate the serine/threonine protein phosphatase 2A (PP2A), and these small-molecule activators of PP2A (SMAPs) induce apoptosis and inhibit tumor growth in numerous cancer models. Based on these findings, this project aimed to identify drug combinations with our SMAP that could drive optimal anticancer activity. Methods: We first turned to global shotgun phosphoproteomics to compare the signaling response signatures of our SMAP against a combination of a MEK inhibitor (MEKi) and an AKT inhibitor (AKTi). We then applied Kinase-Substrate Enrichment Analysis (KSEA) to extract key diverging biologic patterns between these two arms, with the goal of identifying distinct pathways that are inhibited in each condition. These results, in turn, could provide insight to differences between phosphatase activation versus kinase inhibition. Results: KSEA profiling revealed distinct signaling responses between the two arms. Notably, the kinase inhibitors caused robust downregulation of the MAPK signaling pathway, whereas SMAP treatment showed limited involvement of that cascade. Thus, we hypothesized that a combination of SMAP + MEKi would yield enhanced anticancer response compared to either single agent. Subsequent murine xenograft testing demonstrated superior tumor response with SMAP + MEKi versus either compound alone. Conclusion: This project offers a phosphoproteomics-level glimpse to the signaling effects between phosphatase activation compared to kinase inhibition. The data, in turn, could be used for rational drug combination design to improve antitumor therapy. Citation Format: Danica D. Wiredja, Peter Liao, Jaya Sangodkar, Daniela Schlatzer, Mark R. Chance, Goutham Narla. Phosphoproteomics-guided anticancer drug combination design with a novel small-molecule PP2A activator [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 2698.