RT Journal Article
SR Electronic
T1 IκB kinase β inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL<sup>+</sup> cells
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 391
OP 397
DO 10.1158/1535-7163.MCT-07-0305
VO 7
IS 2
A1 Duncan, Elizabeth A.
A1 Goetz, Christine A.
A1 Stein, Sarah J.
A1 Mayo, Katie J.
A1 Skaggs, Brian J.
A1 Ziegelbauer, Karl
A1 Sawyers, Charles L.
A1 Baldwin, Albert S.
YR 2008
UL http://mct.aacrjournals.org/content/7/2/391.abstract
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]