Loss of p53 impedes the antileukemic response to BCR-ABL inhibition

Wendel, Hans-Guido, de Stanchina, Elisa, Cepero, Enriqué, Ray, Sagarika, Emig, Michael, Fridman, Jordan S., Veach, Darren R., Bornmann, William G., Clarkson, Bayard, McCombie, W. Richard, Kogan, Scott C., Hochhaus, Andreas, Lowe, Scott W. (2006) Loss of p53 impedes the antileukemic response to BCR-ABL inhibition. Proceedings of the National Academy of Sciences of the United States of America, 103 (19). pp. 7444-9. ISSN 0027-8424

URL: http://www.ncbi.nlm.nih.gov/pubmed/16651519
DOI: 10.1073/pnas.0602402103

Abstract

Targeted cancer therapies exploit the continued dependence of cancer cells on oncogenic mutations. Such agents can have remarkable activity against some cancers, although antitumor responses are often heterogeneous, and resistance remains a clinical problem. To gain insight into factors that influence the action of a prototypical targeted drug, we studied the action of imatinib (STI-571, Gleevec) against murine cells and leukemias expressing BCR-ABL, an imatinib target and the initiating oncogene for human chronic myelogenous leukemia (CML). We show that the tumor suppressor p53 is selectively activated by imatinib in BCR-ABL-expressing cells as a result of BCR-ABL kinase inhibition. Inactivation of p53, which can accompany disease progression in human CML, impedes the response to imatinib in vitro and in vivo without preventing BCR-ABL kinase inhibition. Concordantly, p53 mutations are associated with progression to imatinib resistance in some human CMLs. Our results identify p53 as a determinant of the response to oncogene inhibition and suggest one way in which resistance to targeted therapy can emerge during the course of tumor evolution.

Item Type: Paper
Uncontrolled Keywords: Animals Cell Line Tumor Disease Progression Drug Resistance, Neoplasm genetics Fusion Proteins bcr-abl metabolism Hematopoietic Stem Cell Transplantation Humans Leukemia drug therapy genetics metabolism pathology Mice Mice Knockout Mutation genetics Neoplasm Transplantation Piperazines/pharmacology Pyrimidines pharmacology Survival Rate Tumor Suppressor Protein p53 deficiency genetics/ metabolism
Subjects: diseases & disorders > cancer
diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > drugs and therapies > imatinib
diseases & disorders > cancer > cancer types > leukemia
CSHL Authors:
Communities: CSHL labs > Lowe lab
CSHL labs > McCombie lab
Depositing User: CSHL Librarian
Date Deposited: 06 Dec 2011 20:57
Last Modified: 11 Apr 2013 19:43
PMCID: PMC1455409
Related URLs:
URI: http://repository.cshl.edu/id/eprint/22929

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