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Research Articles: Therapeutics, Targets, and Development

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

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

Requests for reprints: Albert S. Baldwin, 22-000 Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295. Phone: 919-966-3652; Fax: 919-966-8212. 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 β, 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 β inhibition represents a potential new approach for treatment of Imatinib- or Dasatinib-resistant forms of chronic myelogenous leukemia. [Mol Cancer Ther 2008;7(2):391–7]

Grant support: National Cancer Institute grants CA 73756 and CA75080 (A.S. Baldwin), Leukemia and Lymphoma Society (A.S. Baldwin and C.L. Sawyers), American Cancer Society (E.A. Duncan), and Cancer Research Institute postdoctoral fellowship (C.A. Goetz).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: E.A. Duncan, C.A. Goetz, and S.J. Stein contributed equally to this work. A.S. Baldwin and C.L. Sawyers are investigators of the Waxman Cancer Research Foundation.

Received 5/ 1/07; revised 12/ 5/07; accepted 12/21/07.

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