title: Unlocking the Potential of High-Throughput Drug Combination Assays Using Acoustic Dispensing.
abstract: Assessment of synergistic effects of drug combinations in vitro is a critical part of anticancer drug research. However, the complexities of dosing and analyzing two drugs over the appropriate range of doses have generally led to compromises in experimental design that restrict the quality and robustness of the data. In particular, the use of a single dose response of combined drugs, rather than a full two-way matrix of varying doses, has predominated in higher-throughput studies. Acoustic dispensing unlocks the potential of high-throughput dose matrix analysis. We have developed acoustic dispensing protocols that enable compound synergy assays in a 384-well format. This experimental design is considerably more efficient and flexible with respect to time, reagent usage, and labware than is achievable using traditional serial-dilution approaches. Data analysis tools integrated in Genedata Screener were used to efficiently deconvolute the combination compound mapping scheme and calculate compound potency and synergy metrics. We have applied this workflow to evaluate interactions among drugs targeting different nodes of the mitogen-activated protein kinase pathway in a panel of cancer cell lines.
authors.affiliation: Department of Biochemical and Cellular Pharmacology, San Francisco, CA, USA.
authors.forename: Grace Ka Yan
authors.initials: GK
authors.lastname: Chan
authors.affiliation: Department of Immunology, Tissue Growth and Repair Biomarker Development, Genentech, South San Francisco, CA, USA.
authors.forename: Stacy
authors.initials: S
authors.lastname: Wilson
authors.affiliation: Department of Biochemical and Cellular Pharmacology, San Francisco, CA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Department of Biochemical and Cellular Pharmacology, San Francisco, CA, USA jmoffat@gene.com.
authors.forename: John G
authors.initials: JG
authors.lastname: Moffat
mesh_terms: D000162:Acoustics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D020811:Biomedical Technology / Q000379:methods*; D004338:Drug Combinations; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*; D012996:Solutions
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D012996:Solutions
keywords: HTS; acoustic droplet ejection; automated biology; high-throughput screening; informatics and software; screening data analysis