A screen to identify drug resistant variants to target-directed anti-cancer agents

Mohammad Azam, Tal Raz, Valentina Nardi, Sarah L. Opitz, George Q. Daley*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

The discovery of oncogenes and signal transduction pathways important for mitogenesis has triggered the development of target-specific small molecule anti-cancer compounds. As exemplified by imatinib (Gleevec), a specific inhibitor of the Chronic Myeloid Leukemia (CML)-associated Bcr-Abl kinase, these agents promise impressive activity in clinical trials, with low levels of clinical toxicity. However, such therapy is susceptible to the emergence of drug resistance due to amino acid substitutions in the target protein. Defining the spectrum of such mutations is important for patient monitoring and the design of next-generation inhibitors. Using imatinib and BCR/ABL as a paradigm for a drug-target pair, we recently reported a retroviral vector-based screening strategy to identify the spectrum of resistance-conferring mutations. Here we provide a detailed methodology for the screen, which can be generally applied to any drug-target pair.

Original languageAmerican English
Pages (from-to)204-210
Number of pages7
JournalBiological Procedures Online
Volume5
Issue number1
DOIs
StatePublished - 2003
Externally publishedYes

Keywords

  • Chronic myeloid leukemia
  • Drug resistance
  • Genes, ABL

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