Article

IB kinase inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL⁺ cells

^{1 1}Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine; ²Department of Biology and ³Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina; ⁴University of California-Los Angeles School of Medicine, Los Angeles, California; ⁵Bayer Healthcare, Wuppertal, Germany; and ⁶Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York

^* To whom correspondence should be addressed. E-mail: abaldwin{at}med.unc.edu.

	Abstract

Chronic myelogenous leukemia is a malignant disease of the hematopoietic stem cell compartment, which is characterized by expression of the BCR-ABL fusion protein. Expression of BCR-ABL allows myeloid cells to grow in the absence of the growth factors interleukin-3 and granulocyte-macrophage colony-stimulating factor. The tyrosine kinase activity of BCR-ABL constitutively activates signaling pathways associated with Ras and its downstream effectors and with the Jak/STAT pathway. Additionally, we reported previously that BCR-ABL activates the transcription factor nuclear factor-B (NF-B) in a manner dependent on Ras and that inhibition of NF-B by expression of a modified form of IB blocked BCR-ABL-driven tumor growth in a xenograft model. Here, we show that a highly specific inhibitor of IB kinase , a key upstream regulator of the NF-B pathway, induces growth suppression and death in cells expressing wild-type, Imatinib-resistant, or the T315I Imatinib/Dasatinib-resistant forms of BCR-ABL. Cell cycle variables were not affected by this compound. These data indicate that blockage of BCR-ABL-induced NF-B activation via IB kinase inhibition represents a potential new approach for treatment of Imatinib- or Dasatinib-resistant forms of chronic myelogenous leukemia. [Mol Cancer Ther 2008;7(2):OF1–7]

Key Words: BCR-ABL, Imatinib, Dasatinib, IKK inhibition, NF-B

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