Open AccessContribution of BCR–ABL‐independent activation of ERK1/2 to acquired imatinib resistance in K562 chronic myeloid leukemia cells
Author(s) -
Nambu Takeru,
Araki Norie,
Nakagawa Aiko,
Kuniyasu Akihiko,
Kawaguchi Tatsuya,
Hamada Akinobu,
Saito Hideyuki
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2009.01365.x
Subject(s) - imatinib , k562 cells , cancer research , myeloid leukemia , imatinib mesylate , tyrosine kinase , abl , breakpoint cluster region , chronic myelogenous leukemia , tyrosine kinase inhibitor , biology , leukemia , chemistry , immunology , signal transduction , microbiology and biotechnology , biochemistry , receptor , cancer , genetics
BCR–ABL tyrosine kinase, generated from the reciprocal chromosomal translocation t(9;22), causes chronic myeloid leukemia (CML). BCR–ABL is inhibited by imatinib; however, several mechanisms of imatinib resistance have been proposed that account for loss of imatinib efficacy in patients with CML. Previously, we showed that overexpression of the efflux drug transporter P‐glycoprotein partially contributed to imatinib resistance in imatinib‐resistant K562 CML cells having no BCR–ABL mutations. To explain an additional mechanism of drug resistance, we established a subclone (K562/R) of the cells and examined the BCR–ABL signaling pathway in these and wild‐type K562 (K562/W) cells. We found the K562/R cells were 15 times more resistant to imatinib than their wild‐type counterparts. In both cell lines, BCR–ABL and its downstream signaling molecules, such as ERK1/2, ERK5, STAT5, and AKT, were phosphorylated in the absence of imatinib. In both cell lines, imatinib effectively reduced the phosphorylation of all the above, except ERK1/2, whose phosphorylation was, interestingly, only inhibited in the wild‐type cells. We then observed that phospho‐ERK1/2 levels decreased in the presence of siRNA targeting BCR–ABL, again, only in the K562/W cells. However, using an ERK1/2 inhibitor, U0126, we found that we could reduce phospho‐ERK1/2 levels in K562/R cells and restore their sensitivity to imatinib. Taken together, we conclude that the BCR–ABL‐independent activation of ERK1/2 contributes to imatinib resistance in K562/R cells, and that ERK1/2 could be a target for the treatment of CML patients whose imatinib resistance is due to this mechanism. ( Cancer Sci 2009)