A streamlined search technology for identification of synergistic drug combinations

Sci Rep. 2015 Sep 29;5:14508. doi: 10.1038/srep14508.

Abstract

A major key to improvement of cancer therapy is the combination of drugs. Mixing drugs that already exist on the market may offer an attractive alternative. Here we report on a new model-based streamlined feedback system control (s-FSC) method, based on a design of experiment approach, for rapidly finding optimal drug mixtures with minimal experimental effort. We tested combinations in an in vitro assay for the viability of a renal cell adenocarcinoma (RCC) cell line, 786-O. An iterative cycle of in vitro testing and s-FSC analysis was repeated a few times until an optimal low dose combination was reached. Starting with ten drugs that target parallel pathways known to play a role in the development and progression of RCC, we identified the best overall drug combination, being a mixture of four drugs (axitinib, erlotinib, dasatinib and AZD4547) at low doses, inhibiting 90% of cell viability. The removal of AZD4547 from the optimized drug combination resulted in 80% of cell viability inhibition, while still maintaining the synergistic interaction. These optimized drug combinations were significantly more potent than monotherapies of all individual drugs (p < 0.001, CI < 0.3).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Axitinib
  • Benzamides / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dasatinib / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Epithelial Cells / drug effects*
  • Epithelial Cells / pathology
  • Erlotinib Hydrochloride / pharmacology*
  • Humans
  • Imidazoles / pharmacology*
  • Indazoles / pharmacology*
  • Kidney / drug effects
  • Kidney / pathology
  • Piperazines / pharmacology*
  • Pyrazoles / pharmacology*

Substances

  • AZD4547
  • Antineoplastic Agents
  • Benzamides
  • Drug Combinations
  • Imidazoles
  • Indazoles
  • Piperazines
  • Pyrazoles
  • Axitinib
  • Erlotinib Hydrochloride
  • Dasatinib