Blood online
Home About Blood Authors Subscriptions Permission Advertising Public Access contact us
 

 
Advanced
Current Issue
First Edition
Archives
Submit to Blood
Search
American Society of Hematology
Meeting Abstracts
Email Alerts
 Blood, 15 September 2007, Vol. 110, No. 6, pp. 2102-2109.
Prepublished online as a Blood First Edition Paper on May 29, 2007; DOI 10.1182/blood-2006-12-064907.

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental Figures
Right arrow All Versions of this Article:
blood-2006-12-064907v1
110/6/2102    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Right arrow Rights and Permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Raz, T.
Right arrow Articles by Daley, G. Q.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Raz, T.
Right arrow Articles by Daley, G. Q.
Related Collections
Right arrow Oncogenes and Tumor Suppressors
Right arrow Signal Transduction
Right arrow Neoplasia
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

arrow to previous article Previous Article  |  Table of Contents  |  Next Article next article arrow

NEOPLASIA

Farnesyl transferase inhibitor resistance probed by target mutagenesis

Tal Raz1, Valentina Nardi1, Mohammad Azam1, Jorge Cortes2, and George Q. Daley1

1 Division of Hematology/Oncology, Children's Hospital Boston, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA; 2 M. D. Anderson Cancer Center, Houston, TX

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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?




click for free articles
home about blood authors subscriptions permissions advertising public access contact us
Sponsor: Genentech BioOncology and and Biogen Idec
Blood Online is supported in part by
Genentech BioOncology and Biogen Idec
  Copyright © 2007 by American Society of Hematology         Online ISSN: 1528-0020