Farnesyl transferase inhibitor resistance probed by target mutagenesis

Tal Raz, Valentina Nardi, Mohammad Azam, Jorge Cortes, George Q. Daley

Research output: Contribution to journalArticle

Abstract

Mutation in the target oncoprotein is a common mechanism of resistance to tyrosine kinase inhibitors, as exemplified by the many BCR/ABL mutations that thwart imatinib activity in patients with chronic myelogenous leukemia. It remains unclear whether normal cellular protein targets of chemotherapeutics will evolve drug resistance via mutation to a similar extent. We conducted an in vitro screen for resistance to lonafarnib, a farnesyl protein transferase inhibitor that blocks prenylation of a number of proteins important in cell proliferation, and identified 9 mutations clustering around the lonafarnib binding site. In patients treated with a combination of imatinib and lonafarnib, we identified farnesyl protein transferase mutations in residues identified in our screen. Substitutions at Y361 were found in patients prior to treatment initiation, suggesting that these mutants might confer a proliferative advantage to leukemia cells, which we were able to confirm in cell culture. In vitro mutagenesis of normal cellular enzymes can be exploited to identify mutations that confer chemotherapy resistance to novel agents.

Original languageEnglish (US)
Pages (from-to)2102-2109
Number of pages8
JournalBlood
Volume110
Issue number6
DOIs
StatePublished - Sep 15 2007
Externally publishedYes

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Mutagenesis
Transferases
Mutation
Proteins
Chemotherapy
Oncogene Proteins
Cell proliferation
Cell culture
Protein-Tyrosine Kinases
Prenylation
Substitution reactions
Binding Sites
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Drug Resistance
Cluster Analysis
Leukemia
Enzymes
Cell Culture Techniques
Cell Proliferation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Farnesyl transferase inhibitor resistance probed by target mutagenesis. / Raz, Tal; Nardi, Valentina; Azam, Mohammad; Cortes, Jorge; Daley, George Q.

In: Blood, Vol. 110, No. 6, 15.09.2007, p. 2102-2109.

Research output: Contribution to journalArticle

Raz, Tal ; Nardi, Valentina ; Azam, Mohammad ; Cortes, Jorge ; Daley, George Q. / Farnesyl transferase inhibitor resistance probed by target mutagenesis. In: Blood. 2007 ; Vol. 110, No. 6. pp. 2102-2109.
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