Ranking Differential Drug Activities from Dose-Response Synthetic Lethality Screens.
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.
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Rajarshi
R
Guha
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Lesley A
LA
Mathews Griner
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Jonathan M
JM
Keller
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Xiaohu
X
Zhang
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
David
D
Fitzgerald
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Antonella
A
Antignani
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Ira
I
Pastan
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Craig J
CJ
Thomas
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA ferrerm@mail.nih.gov.
Marc
M
Ferrer
D001427:Bacterial Toxins / Q000037:antagonists & inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005098:Exotoxins / Q000037:antagonists & inhibitors; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D054852:Small Molecule Libraries / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D000072020:Synthetic Lethal Mutations / Q000235:genetics*
D001427:Bacterial Toxins; D005098:Exotoxins; D054852:Small Molecule Libraries; C541974:immunotoxin HA22
immunotoxin; qHTS; ranking; synthetic lethal screen