Abstract PR09: Targeting the MYC-WDR5 nexus in colorectal cancer (2017)

Abstract The overexpression of c-MYC is one of the most prominent alterations in colorectal cancer (CRC), featuring in roughly 70% of colorectal adenocarcinomas. Induction of MYC is a critical event in the development and progression of CRC, as it causes a variety of biological responses, including cell cycle progression, cellular growth, and differentiation. The contribution of the MYC oncoprotein to the pathogenesis of CRC is evidenced by its widespread overexpression and its correlation with poor patient survival, and by observations that deletion of c-Myc—or mutation of the β-catenin/TCF/LEF enhancer upstream of c-Myc—dramatically reduces intestinal tumor burden in ApcMin mice. Despite the pervasive involvement of MYC in CRC, and a wealth of studies in other systems demonstrating that genetic inhibition of MYC promotes frank tumor regression, MYC is generally considered undruggable—as of yet, no drug-like molecules have been discovered that are capable of blocking MYC function in cancer cells. Recently, however, we devised a novel approach to target MYC, based on our observations that binding of MYC to its target genes in the context of chromatin is dependent on interaction with the chromatin-scaffolding protein WDR5. We have proposed that target gene recognition by MYC is an avidity-based mechanism that involves two critical sets of interactions: one between MYC/MAX heterodimers and DNA, and another between MYC and chromatin-bound WDR5. We showed that interaction with WDR5 is necessary for the ability of MYC to function as a transcription factor and oncoprotein. Importantly, structural analysis revealed that MYC directly binds WDR5 by engaging a shallow, hydrophobic, cleft on the surface of WDR5 that is well-suited for drug discovery. The tractability of the MYC–WDR5 interface as a vehicle for drug discovery should make it possible to identify drug-like molecules that disrupt interaction of MYC with chromatin and diminish its tumorigenic potential. Fueled by the potential of this discovery, the Fesik and Tansey laboratories collaborate to identify, refine, and validate drug-like molecules that disrupt the MYC–WDR5 interaction, and propose to explore their efficacy as anti-cancer agents. Since the overexpression of MYC is featured in the majority of colorectal adenomas, we will investigate the requirement of the MYC–WDR5 interaction in colorectal carcinoma cell lines and in mice. During the small-molecule discovery phase, an inducible mutant version of MYC will be utilized to determine the effects of loss of the MYC–WDR5 interaction in CRC cell lines and in mice with adenomatous polyps, both further elucidating the biological basis of this interaction, as well as establishing a baseline for effects we should see from on-target small-molecule inhibitors. Through cellular, molecular, and genomic comparison of the effects of genetic versus chemical disruption of the MYC–WDR5 interaction, we will validate on-target action of probe compounds, providing critical information needed to select candidate molecules that will be refined for drug-like properties. Successful completion of this work will generate novel insights into MYC biology, its role in CRC, as well as first-in-class MYC–WDR5 inhibitors validated for their efficacy in CRC. This abstract is also being presented as Poster B18. Citation Format: Audra M. Foshage, Lance R. Thomas, Shaun R. Stauffer, Stephen W. Fesik, William P. Tansey. Targeting the MYC-WDR5 nexus in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr PR09.