Abstract 5256: The identification of fatty acid synthase (FASN) as a candidate oncogene and therapeutic target in neuroblastoma

Abstract

Abstract Neuroblastoma is a common and lethal pediatric cancer. More than half of patients are at high-risk for relapse and die despite intensive therapy; thus presenting an urgent need for new, rationally designed drugs. To address the need for new therapeutic targets we sought to identify metabolic genes that are critical to neuroblastoma growth and survival. We restricted our analysis to a set of 12 metabolic genes that can be targeted therapeutically and had previously been implicated in other cancers. Analysis of 188 primary human neuroblastomas genotyped on the Illumina HumanHap SNP Array identified high-level, unbalanced gain at the FASN locus (17q25) in 23% of tumors. Analysis of FASN mRNA expression in 99 of these primary neuroblastomas using the IlluminaHT Expression Array identified significant increases in FASN expression restricted to high-risk neuroblastomas with amplification of the MYCN oncogene (P=0.0001). Within the subset of high-risk tumors with MYCN amplification, those that harbored FASN DNA copy number gains showed greater FASN mRNA expression than those with two copy FASN DNA. We next tested siRNAs targeted to the set of 12 metabolic genes in a panel of 12 neuroblastoma cell lines. We found that siRNA inhibition of fatty acid synthase (FASN) and hexokinase 2 (HK2) resulted in significant growth inhibition in 9/12 and 6/12 cell lines, respectively, whereas the others showed no appreciable cytotoxicity. Inhibition of FASN resulted in significant growth inhibition and apoptosis in 8/8 neuroblastoma cell lines with MYCN amplification, suggesting a synthetic lethal effect of FASN inhibition in neuroblastomas with MYCN amplification. Taken together, an integrated genomic and functional analytic approach has identified fatty acid synthase, a key enzymatic mediator of de novo fatty acid metabolism, as a candidate oncogene and therapeutic target in neuroblastoma, especially those harboring MYCN amplification. Ongoing analyses of pharmacologic inhibitors of FASN in neuroblastoma cell line animal models, including impact on global lipidomic profiles will be reported. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5256.