Abstract 2779: Rapid drug target ranking system developed from a systematic analysis of cancer genomic data from the Oncomine™ knowledgebase identifies an oncogenic role for the NFE2L2 pathway in multiple cancer types
Authors: Sean Eddy, Mary Ellen Urick, Mark Tomilo, Armand Bankhead, Dan Rhodes, Emma T. Bowden
Journal: Cancer Research (2014)

Abstract Late stage drug attrition rates in oncology remain higher than other therapeutic areas. To reduce attrition, it is critical to identify appropriate drug targets and pre-clinical models. Next-generation sequencing (NGS) is poised to accelerate the discovery of new drug targets through identification of genomic markers of response and identification of models to characterize candidate drivers. To maximize the value of NGS, it is imperative to develop data analysis/interpretation solutions that accurately assess genomic aberrations, delineate driver alterations from passengers, annotate alterations for clinical relevance and integrate alterations by gene and pathway. Here, we present our framework for the systematic analysis of thousands of clinical NGS samples as well as expertly curated oncology data for the purpose of identifying candidate drug targets. Our methodology was developed through a systematic interrogation of genomic aberrations in a training set of gold standard oncogenes such as EGFR and PIK3CA, and tumor suppressors such as TP53 and PTEN. The resulting platform was used to rank genes through an assessment of driver genomic aberrations, associations with patient survival, and potential clinical actionability. Using this framework, we found supporting evidence implicating NFE2L2 as an oncogene. Recurrent NFE2L2 mutations were found in multiple cancer types and associated with poor outcome in head and neck squamous cell carcinoma. Recurrent mutations were identified in: 14.0% of squamous cell lung carcinoma, 12.5% of hepatocellular carcinoma, 11.1% of infiltrating bladder urothelial carcinoma, 7.7% of cervical squamous carcinoma, and 4% of head and neck squamous cell carcinoma. We also investigated KEAP1, a repressor of NFE2L2 activity. Mutations in KEAP1 tended to localize within the NFE2L2 binding domains and displayed evidence of mutual exclusivity with NFE2L2 recurrent mutations. KEAP1 mutations were identified in 14% of lung adenocarcinoma, 13.5% of squamous cell lung carcinoma, 7.4% of infiltrating bladder urothelial carcinoma, and 4% of hepatocellular carcinoma. Genes up-regulated in patients with mutations in either NFE2L2 or KEAP1 in squamous cell lung carcinoma included many direct NFE2L2 target genes (e.g. GCLC, GCLM, NQO1). Genes up-regulated in NFE2L2 or KEAP1 mutant patients significantly associated with genes up-regulated in cell lines resistant to chemotherapy. Using Oncomine™ database curated data and cell line exome data we were able to identify cell lines that were representative of clinical populations containing these mutations. We have provided proof of concept identification of a potentially clinically relevant candidate driver gene using a novel systematic analysis of cancer genomic data. Citation Format: Sean Eddy, Mary Ellen Urick, Mark Tomilo, Armand Bankhead, Dan Rhodes, Emma T. Bowden. Rapid drug target ranking system developed from a systematic analysis of cancer genomic data from the Oncomine™ knowledgebase identifies an oncogenic role for the NFE2L2 pathway in multiple cancer types. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2779. doi:10.1158/1538-7445.AM2014-2779