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Modernizing the NCI60 Cell Line Screen for Phenotypic Drug Discovery in the 21st Century
Gianna M Colombo1,2,3, Steven M Corsello1,2,3
1Department of Medicine, Stanford School of Medicine, Stanford, California.
Abstract:
Over the past three decades, high-throughput phenotypic cancer cell line screens have revealed unanticipated small-molecule activities and illuminated connections between tumor genotypes and anticancer efficacy. Founded in 1984, the National Cancer Institute's "NCI60" screen laid the conceptual groundwork for the contemporary landscape of phenotypic drug discovery. NCI60 first operated as a primary bioactivity screen, but molecular characterization of the NCI60 cell line panel and development of a small-molecule sensitivity pattern recognition algorithm (called "COMPARE") have enabled subsequent studies into drug mechanisms of action and biomarker identification. In this issue of Cancer Research, Kunkel and colleagues report an updated version of the NCI60 screen, dubbed "HTS384" NCI60, that better aligns with current cell proliferation assay standards and has higher throughput. Changes include the use of a 384-well plate format, automated laboratory equipment, 3 days of compound exposure, and a CellTiter-Glo luminescent endpoint. To confirm that data from the HTS384 and classic NCI60 screen are comparable, the authors tested a library of 1,003 anticancer agents using both protocols and applied COMPARE to analyze patterns of cell line sensitivities. More than three dozen groups of targeted therapies showed high comparability between screens. Modernization of NCI60, and closer integration with other large-scale pharmacogenomic screens and molecular feature sets, will help this public screening service remain pertinent for cancer drug discovery efforts for years to come. See related article by Kunkel et al., p. 2403.
Insights
The National Cancer Institute
Area of Science:
- Cancer Research
- Pharmacogenomics
- Drug Discovery
Background:
- The National Cancer Institute's (NCI60) phenotypic cancer cell line screen, established in 1984, pioneered drug discovery by linking small-molecule activities to tumor genotypes.
- Molecular characterization of the NCI60 panel and the COMPARE algorithm enabled studies on drug mechanisms and biomarker identification.
Purpose of the Study:
- To report an updated, higher-throughput version of the NCI60 screen, named HTS384 NCI60, which aligns with current cell proliferation assay standards.
- To validate the comparability of data generated by the HTS384 NCI60 and the classic NCI60 screen.
Main Methods:
- The updated HTS384 NCI60 screen utilizes a 384-well plate format, automated equipment, a 3-day compound exposure, and a CellTiter-Glo luminescent endpoint.
- A library of 1,003 anticancer agents was tested using both HTS384 NCI60 and classic NCI60 protocols.
- The COMPARE algorithm was applied to analyze cell line sensitivity patterns from both screening methods.
Main Results:
- The HTS384 NCI60 screen demonstrated high throughput and alignment with current assay standards.
- Comparisons using the COMPARE algorithm showed high concordance between the HTS384 NCI60 and classic NCI60 screens for over three dozen groups of targeted therapies.
- The updated screen maintains the integrity of the original NCI60 data.
Conclusions:
- The modernized HTS384 NCI60 screen enhances the NCI60's utility for cancer drug discovery.
- Closer integration with other large-scale pharmacogenomic screens and molecular data will ensure the continued relevance of this public screening service.
- This updated platform facilitates ongoing efforts in identifying novel anticancer agents and understanding their mechanisms.
