PT  - JOURNAL ARTICLE
AU  - Duncan, Elizabeth A.
AU  - Goetz, Christine A.
AU  - Stein, Sarah J.
AU  - Mayo, Katie J.
AU  - Skaggs, Brian J.
AU  - Ziegelbauer, Karl
AU  - Sawyers, Charles L.
AU  - Baldwin, Albert S.
TI  - IκB kinase β inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL<sup>+</sup> cells
AID  - 10.1158/1535-7163.MCT-07-0305
DP  - 2008 Feb 01
TA  - Molecular Cancer Therapeutics
PG  - 391--397
VI  - 7
IP  - 2
4099  - http://mct.aacrjournals.org/content/7/2/391.short
4100  - http://mct.aacrjournals.org/content/7/2/391.full
SO  - Mol Cancer Ther2008 Feb 01; 7
AB  - 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-κB (NF-κB) in a manner dependent on Ras and that inhibition of NF-κB by expression of a modified form of IκBα blocked BCR-ABL-driven tumor growth in a xenograft model. Here, we show that a highly specific inhibitor of IκB kinase β, a key upstream regulator of the NF-κB 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-κB activation via IκB 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]