Abstract 5818: Disrupting the Aurora kinase A interactome in pediatric cancer

Abstract

Abstract Neuroblastoma is the most common extra-cranial solid tumor of childhood. Amplification of the MYCN proto-oncogene occurs in 50% of the high-risk neuroblastoma and indicates an aggressive and lethal form of the disease. As a transcription factor with no apparent small-molecule surfaces, direct inhibition of MYCN has proven challenging. Proteolytic cleavage of MYCN is regulated in part by an activity-independent scaffold function of Aurora Kinase A (AURKA). The dynamic expression and activation of AURKA allows for precise cell cycle regulation of several substrates identified by protein-protein interaction studies that are also viable anti-cancer targets, such as the aforementioned MYCN oncoprotein. Utilizing co-immunopreciptation, flow cytometry, and other pertinent cell biology techniques, we aim to delineate a novel mechanism of targeting the AURKA interactome by conformation disruption of AURKA. We have recently described a neoteric class of confirmation disrupting “amphosteric” inhibitors of AURKA (CD-AURKAi) that orthosterically inhibit the ATP-binding pocket to dramatically disrupt the active conformation of AURKA to dissociate and degrade MYCN, a critical oncogenic driver of the pediatric cancer neuroblastoma. In addition to MYCN, our preliminary results show CD532 will also dissociate other oncogenic proteins that interact with AURKA. We hypothesize that conformation disruption of AURKA and subsequent blockade of an array of protein-protein interactions will delineate the roles of AURKA, MYC, and MYCN in the cell cycle and expand the clinical applications for CD-AURKAi in cancer to include non-MYCN driven diseases. Citation Format: Sucheta Mukherjee, Carolyn Tu, Clay Gustafson. Disrupting the Aurora kinase A interactome in pediatric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5818. doi:10.1158/1538-7445.AM2017-5818