Loss of p53 impedes the antileukemic response to BCR-ABL inhibition Journal Article
| Authors: | Wendel, H. G.; de Stanchina, E.; Cepero, E.; Ray, S.; Emig, M.; Fridman, J. S.; Veach, D. R.; Bornmann, W. G.; Clarkson, B.; McCombie, W. R.; Kogan, S. C.; Hochhaus, A.; Lowe, S. W. |
| Article Title: | Loss of p53 impedes the antileukemic response to BCR-ABL inhibition |
| 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. © 2006 by The National Academy of Sciences of the USA. |
| Keywords: | controlled study; leukemia; survival rate; unclassified drug; gene mutation; human cell; mutation; disease course; nonhuman; animal cell; mouse; animals; mice; mice, knockout; imatinib; enzyme inhibition; animal experiment; animal model; hematopoietic stem cell transplantation; antineoplastic activity; drug resistance; drug resistance, neoplasm; cell line, tumor; 6 (2,6 dichlorophenyl) 2 [3 (hydroxymethyl)anilino] 8 methylpyrido[2,3 d]pyrimidin 7(8h) one; chronic myeloid leukemia; pyrimidines; protein p53; cancer therapy; carcinogenesis; cancer resistance; cancer inhibition; oncogene; tumor suppressor gene; disease progression; cancer cell; murinae; tumor suppressor protein p53; targeted therapy; bcr abl protein; piperazines; neoplasm transplantation; phosphotransferase inhibitor; fusion proteins, bcr-abl; mouse model; tumor-suppressor gene |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 103 |
| Issue: | 19 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2006-05-01 |
| Start Page: | 7444 |
| End Page: | 7449 |
| Language: | English |
| DOI: | 10.1073/pnas.0602402103 |
| PUBMED: | 16651519 |
| PROVIDER: | scopus |
| PMCID: | PMC1455409 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 54" - "Export Date: 4 June 2012" - "CODEN: PNASA" - "Source: Scopus" |
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