Abstract C135: Therapeutic targets for MYC-driven cancer.

Abstract

Abstract Drugs directed toward oncoproteins have demonstrated efficacy while avoiding the systemic toxicity associated with standard chemotherapeutics. However, oncoproteins encoding for transcription factors, such as the MYC family, which are broadly implicated in many human cancers, are difficult to inhibit with small molecules or antibody based therapies. Thus, to target MYC-driven cancers, we have taken the approach of identifying druggable genes that exhibit a synthetic lethal relationship with aberrant MYC expression. Using an isogenic cell model system, we identified, via high throughput siRNA screening, more than 100 druggable genes that exhibit a synthetic lethal interaction with MYC (referred to as MYC-synthetic lethal genes, MYC-SL). Among the MYC-SL genes, we focused on casein kinase 1 epsilon (CSNK1e), whose relevance in MYC-driven human cancer was demonstrated by correlation between high levels of CSNK1e expression, MYCN amplification, and poor clinical prognosis in neuroblastoma cases. The requirement of CSNK1e for growth of neuroblastomas with MYCN amplification was validated in vivo by conditional knock-down and via a small molecule inhibitor of its activity. CSNK1e had previously been implicated in the regulation of WNT, however our data also suggest that in neuroblastoma the activity of CSNK1e is a key component of a positive autocrine circuit triggered by MYCN amplification that sustains both WNT and SHH pathways. In summary, our work elucidates a broad network of MYC synthetic lethal genes, perhaps a reflection of its widespread effects on gene expression, and demonstrates the power of high throughput siRNA screening as a rapid and unbiased approach to identify a network of synthetic lethal genes and potential new therapeutic targets functionally linked to a previously un-druggable oncogene. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C135.