Drug resistance through mutations and upregulation of secondary signaling pathways, as well as the maintenance of leukemia stem cells, is an ongoing clinical problem in the treatment of patients with chronic myeloid leukemia. Novel therapeutic targets that are able to target cells refractory to current therapies are needed. NF-κB is a promising target for the treatment of CML in the clinic given that BCR-ABL-expressing cells require NF-κB activity for survival (Duncan et al., 2008; Cilloni et al., 2006). Further experiments are required to determine the efficacy of IKKβ inhibition in an in vivo model of CML to account for
potential issues due to cues from the microenvironment and drug metabolism. Toxicity due to IKKβ inhibition is also a concern (Nagashima et al., 2006; Greten et al., 2007; Mankan et al., 2011). More insight into the effects of long-term NF-κB inhibition on normal
hematopoiesis is required to determine if the benefits out weight the costs of IKKβ inhibition if drug-resistant CML patients.
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CHAPTER II
IKKβ INHIBITION INDUCES CELL DEATH IN IMATINIB-RESISTANT AND T315I DASATINIB-RESISTANT BCR-ABL+ CELLS
This chapter has been adapted from: Duncan EA*, Goetz CA* and Stein SJ* et al. IKKβ Inhibition Induces Cell Death in Imatinib-Resistant and T315I Dasatinib-Resistant BCR- ABL+ Cells. Molecular Cancer Therapeutics 2007. 7 (2): 391-397.
*These authors contributed equally to this work.