Abstract 5475: Interrogation of NCI-60 patterns of growth inhibition in conjunction with investigational oncology agents kinase profiling for the elucidation of mechanistic targets

Abstract

Abstract As oncology treatment moves toward personalized targeted therapeutic agents, the NCI-60 human tumor cell line panel is an ideal community-wide tool to further understanding of the disease and molecular targets of new agents. The panel includes cell lines from nine tumor types, and is extremely well characterized at the molecular level, enabling interrogation of patterns of growth inhibition by a set of targeted investigational oncology agents looking for characteristics of the cell lines that determine sensitivity. We have used a number of online tools to enable data analysis, including COMPARE (http://dtp.nci.nih.gov/compare/), which provided the identification of compounds and/or genes that have highly correlated response patterns for any selected ‘seed’ compound. These data enable comparisons between drug sensitivity profiles that lead to the elucidation of common mechanistic targets or pathways, associations with potential response biomarkers, the confirmation of mechanism of action or identification of novel mechanisms, and the uncovering of unexpected “off-target” activities. For example, using the allosteric Akt inhibitor MK-2206 as the seed compound, response patterns for the ATP-competitive Akt inhibitors PF-4173640 (0.84), GDC-0068 (0.80), AZD-5363 (0.83), GSK-690693 (0.67), and CCT-128930 (0.69) are highly correlated. In addition, examination of the response profile for vandetinib produced a set of highly correlative agents including the corresponding EGFR inhibitors sapatinib (0.81) and AEE-788 (0.83), as well as the recently FDA-approved BTK inhibitor, ibrutinib (0.72) and the SRC inhibitor, AZD-0530 (0.74). Not surprisingly, kinase profiling of these 5 agents (0.5 uM) showed >90% inhibition of EGFR in all cases. In a third example, the BRAF V600E mutated cell lines were found to be sensitive to the bcr-abl inhibitors bafetinib and rebastinib, similarly to vemurafenib. This association suggested BRAF inhibitory activity for the former agents, which was confirmed through kinase profiling. Moreover, the NCI-60 response pattern for the androgen receptor modulator AZD-3514 has a high correlation with the BET bromodomain inhibitors JQ-1 (0.77), I-Bet-151 (0.80), and I-Bet-762 (0.78), suggesting a commonality of target/pathway for these compounds. Further correlations, associations and hypotheses generated from interrogating the compound response patterns, gene expression profiles, mutations and other characteristics will be presented. Funded by NCI Contract No. HHSN261200800001E. Citation Format: Joel Morris, Mark Kunkel, Eric Polley, Susan Holbeck, Anne Monks, David Evans, Annamaria Rapisarda, Jerry Collins, Beverly Teicher. Interrogation of NCI-60 patterns of growth inhibition in conjunction with investigational oncology agents kinase profiling for the elucidation of mechanistic targets. [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 5475. doi:10.1158/1538-7445.AM2014-5475