Abstract 4884: Targeted investigational oncology agents (IOA) in the NCI60: a phenotypic systems-based resource

Abstract

Abstract The NCI60 human tumor cell line panel is a useful tool in the discovery and development of new anticancer agents. The publicly available cell-line characterization and compound screening data from the NCI60 screen have contributed to identifying cellular mechanisms of potential new anticancer agents. Mean-graph sensitivity/resistance patterns in the NCI60 screen serve as a fingerprint for molecular target identification and mechanism of action (MOA). A new NCI60 resource was developed based on screening of 175 FDA-approved oncology drugs (AOD) plus >825 investigational oncology agents (IOA), representing >250 therapeutic targets and MOAs. Compounds targeting different components in a biochemical pathway tend to show high correlations in their GI50 patterns through COMPARE analysis forming clusters with similar NCI60 mean-graph patterns. COMPARE evaluation of compounds that target components in the PI3K/AKT/mTOR pathway form correlation clusters linked by both target and pathway. Only 3 of 15 AKT inhibitors in the IOA set are not found in the connected cluster with a COMPARE correlation of 0.7 including the multi-kinase inhibitors perifosine and AT-13148. The AKT cluster includes both allosteric (MK-2206) and competitive inhibitors highlighting the NCI60 is a functional cell assay. More than 75% of PI3K inhibitors (32/42 agents), including the selective PI3K alpha and PI3K beta inhibitors, form a highly connected cluster at a 0.7 COMPARE correlation. The heat map view showed that >50% of the non-connected PI3K outliers were inactive in the NCI60 assay. The mTOR inhibitors (12/20) form a connected cluster at 0.7 COMPARE correlation, with half of the non-connected mTOR singletons representative of the rapamycin class of inhibitors. The BRAF/MEK/ERK pathway compounds (37) form a highly connected correlation cluster (13/15 BRAF, 14/15 MEK, 8/9 ERK inhibitors) at a 0.75 COMPARE correlation. The NCI60 heat maps for BRAF inhibitors show a consistent pattern of the melanoma cell lines and 2 of the colon cancer lines (COLO 205, HT29). The ERK inhibitors display sensitivity patterns similar to the BRAF agents with additional activity observed against a leukemia (HL-60), ovarian (OVCAR-5) and renal (A498) cell line and 3 other colon cell lines (HCC-298, HCT-116, SW-620). This data analysis resource will be available to the public (https://ioa.cancer.gov). NCI60 compound suppliers can incorporate their test compound(s) data to use the interactive visualization tools with AOD and IOA agents. This project was funded in part with federal funds from the NCI, NIH, under Contract # 75N91019D00024/75N91020F00003. Citation Format: Joel Morris, Mark W. Kunkel, Stephen L. White, Donn G. Wishka, Omar D. Lopez, Lori Bowles, Penny Sellers, Patricia Ramsey, Julie Grams, Tiffany Rohrer, Karen Martin, Thomas Dexheimer, Dmitriy Sonkin, John D. Williams, Jerry M. Collins, James H. Doroshow, Beverly A. Teicher. Targeted investigational oncology agents (IOA) in the NCI60: a phenotypic systems-based resource. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4884.