Abstract 1030: Metabolic reprogramming caused by mutations of the Fbw7 ubiquitin ligase in colorectal cancer

Abstract

Abstract Fbw7 is an evolutionary conserved F box protein that functions as a substrate adapter for the Skp1-Cullin 1-F box (SCF) E3 ubiquitin ligase complex. Fbw7 is also a tumor suppressor gene that is mutated in diverse human cancers. Many Fbw7 substrates are oncogenic transcription factors, including c-Myc, Notch, and Jun. Cancer-associated Fbw7 mutations diminish its ability to interact with substrates, which results in inappropriate oncoprotein accumulation. One of the significant challenges for understanding the consequences of Fbw7 mutations in tumors is that Fbw7 coordinately regulates approximately two dozen broadly-acting transcription factors. To address this problem, we used novel computational methods to analyze TCGA gene expression datasets to derive transcriptional signatures that could predict a tumor’s Fbw7 mutational status; these signatures were then analyzed for enrichment of genes involved in specific biological processes. We found that genes associated with mitochondrial function were highly predictive of Fbw7 mutations across several tumor types, suggesting that metabolic reprogramming is a crucial oncogenic consequence of Fbw7 mutations. We validated this prediction by creating isogenic colorectal cancer cells with normal or mutant Fbw7 alleles. We found that mitochondrial signature genes are elevated in Fbw7 mutant cells, which also exhibit increased oxidative metabolism. Moreover, metabolomic studies revealed deregulation of other metabolic pathways in Fbw7-mutant cells, including amino acid and nucleotide biosynthesis. These data suggest that metabolic vulnerabilities may represent novel therapeutic targets in Fbw7-associated cancers. Citation Format: Ryan J. Davis, Mehmet Gonen, David Hockenbery, Adam Margolin, Bruce E. Clurman. Metabolic reprogramming caused by mutations of the Fbw7 ubiquitin ligase in colorectal 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 1030. doi:10.1158/1538-7445.AM2017-1030