Loss of p53 impedes the antileukemic response to BCR-ABL inhibition.
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.
Wendel
Hans-Guido
HG
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
de Stanchina
Elisa
E
Cepero
Enriqué
E
Ray
Sagarika
S
Emig
Michael
M
Fridman
Jordan S
JS
Veach
Darren R
DR
Bornmann
William G
WG
Clarkson
Bayard
B
McCombie
W Richard
WR
Kogan
Scott C
SC
Hochhaus
Andreas
A
Lowe
Scott W
SW
D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl