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Donato, Ji Yuan Wu, Jonathan Stapley, Gary Gallick, Hui Lin, Ralph Arlinghaus, and Moshe Talpaz From the Departments of Bioimmunotherapy, Cancer Biology, and Molecular Pathology, University of Texas, M D Anderson Cancer Center, Houston, TX. Clinical studies have shown that the tyrosine kinase inhibitor STI571 effectively controls BCR-ABL-positive chronic myelogenous leukemia (CML). However, disease progression while on STI571 therapy has been reported, suggesting de novo or intrinsic resistance to BCR-ABL-targeted therapy. To investigate possible mediators of acquired STI571 resistance, K562 cells resistant to 5 µM STI571 (K562-R) were cloned and compared to the parental cell population. K562-R cells had reduced BCR-ABL expression and limited activation of BCR-ABL signaling cascades (Stat 5, CrkL, MAPK). STI571 failed to activate caspase cascades or to suppress expression of survival genes (bcl-xL) in resistant cells. Gene sequencing and tyrosine kinase activity measurements demonstrated that K562-R cells retained wild-type and active BCR-ABL tyrosine kinase that was inhibitable by in vitro incubation with STI571, suggesting that BCR-ABL was not coupled to proliferation or survival of K562-R cells. The src-related kinase LYN was highly overexpressed and activated in K562-R cells, and its inhibition reduced proliferation and survival of K562-R cells while having limited effects of K562 cells. Specimens taken from patients with advanced CML that progressed on STI571 therapy also were analyzed for LYN kinase expression, and they were found to be elevated to a level similar to that of K562-R cells. Comparison of samples from patients taken prior to and following STI571 failure suggested that expression and/or activation of LYN/HCK occurs during disease progression. Together, these results suggest that acquired STI571 resistance may be associated with BCR-ABL independence and mediated in part through overexpression of other tyrosine kinases. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Eley, F. R. Luo, S. Agrawal, A. Sanil, J. Manning, T. Li, A. Blackwood-Chirchir, and R. Bertz Phase I Study of the Effect of Gastric Acid pH Modulators on the Bioavailability of Oral Dasatinib in Healthy Subjects J. Clin. Pharmacol., June 1, 2009; 49(6): 700 - 709. [Abstract] [Full Text] [PDF] D. J. Kominsky, J. Klawitter, J. L. Brown, L. G. Boros, J. V. Melo, S. G. Eckhardt, and N. J. Serkova Abnormalities in Glucose Uptake and Metabolism in Imatinib-Resistant Human BCR-ABL-Positive Cells Clin. Cancer Res., May 15, 2009; 15(10): 3442 - 3450. [Abstract] [Full Text] [PDF] S.-F. 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