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J Biomol Screen. 2016 Oct;21(9):942-55. doi: 10.1177/1087057116644890. Epub 2016 Apr 25.

Ranking Differential Drug Activities from Dose-Response Synthetic Lethality Screens.

Author information

1
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
2
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
3
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA ferrerm@mail.nih.gov.

Abstract

Synthetic lethal screens are used to discover new combination treatments for cancer. In traditional high-throughput synthetic lethal screens, compounds are tested at a single dose, and hit selection is based on threshold activity values from the variance of the efficacy of the compounds tested. The limitation of the single-dose screening for synthetic lethal screens is that it does not allow for the robust detection of differential activities from compound collections with a broad range of potencies and efficacies. There is therefore a need to develop screening approaches that enable the identification of compounds with synthetic lethal effects based on changes in both potency and efficacy. Here we describe the implementation of a dose response-based synthetic lethal screen to find drugs that enhance or mitigate the cytotoxic effect of an immunotoxin protein (HA22). We developed a data analysis framework for the selection of compounds with enhancing or mitigating cytotoxic activities based on the use of dose-response parameters. The data analysis framework includes an ensemble ranking approach that allows the use of multiple dose-response parameters in a nonparametric fashion. Quantitative high-throughput screening (HTS) enables the identification of compounds with synthetic lethal activity not identified by single-dose HTS.

KEYWORDS:

immunotoxin; qHTS; ranking; synthetic lethal screen

PMID:
27112173
DOI:
10.1177/1087057116644890
[Indexed for MEDLINE]

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