Abstract IA11: Identification of therapeutic targets for MYC-driven cancers by functional genomics

The development of small molecules targeting MYC oncoproteins specifically in cancer cells has been a challenge, as MYC are DNA binding proteins required for proliferation of normal tissues. To circumvent these difficulties, we identified synthetic lethal interactions with MYC over-expression by high throughput siRNA screening (Toyoshima et al, 2012). Here, we will present validation of specific MYC-synthetic lethal genes (MYC-SL) in MYCN amplified neuroblastoma and ovarian cancer with high level of MYC using both RNAi approaches as well as small molecule inhibitors. To prioritize genes for future drug development, we carried out meta-analysis of genomic tumor data and obtained statistical significant associations between MYC alterations (i.e. gene amplification or overexpression) for selected MYC-SL genes. We also addressed the need of identifying biomarkers to stratify patients with solid tumors for activation of MYC and we will discuss the challenges and potential strategies, with particular focus on ovarian and breast cancers. Finally, to obtain a more global view of critical pathways that MYC-SL genes we performed network analysis of our targets. This analysis revealed that major points of vulnerabilities are linked to transcription and chromatin remodeling processes, DNA repair and cell-cycle checkpoints and metabolic functions. In addition, developmental, signaling and differentiation pathways represent unforeseen dependencies of MYC overexpressing cells. Altogether, these results provide a broad menu for therapeutic interventions to target MYC-driven cancers. *Current affiliation: Tohoku University School of Medicine, Sendai, Japan. Citation Format: Masafumi Toyoshima, In Sock Jang, Silvia Cermelli, Brady Bernard, Carla Grandori. Identification of therapeutic targets for MYC-driven cancers by functional genomics. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr IA11.