Using transcriptome sequencing to identify mechanisms of drug action and resistance

Nat Chem Biol. 2012 Feb 12;8(3):235-7. doi: 10.1038/nchembio.779.

Abstract

Determining mechanisms of drug action in human cells remains a major challenge. Here we describe an approach in which multiple-drug-resistant clones are isolated and transcriptome sequencing is used to find mutations in each clone. Further analysis of mutations common to more than one clone can identify a drug's physiological target and indirect resistance mechanisms, as indicated by our proof-of-concept studies of the cytotoxic anticancer drugs BI 2536 and bortezomib.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Boronic Acids / chemistry
  • Boronic Acids / pharmacology
  • Bortezomib
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / genetics*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics*
  • Pteridines / chemistry
  • Pteridines / pharmacology
  • Pyrazines / chemistry
  • Pyrazines / pharmacology
  • Sequence Analysis, DNA*
  • Transcriptome / genetics*

Substances

  • Antineoplastic Agents
  • BI 2536
  • Boronic Acids
  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • Pteridines
  • Pyrazines
  • Bortezomib
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1