Sensitization of tumor cells to cancer therapy by molecularly targeted inhibition of the inhibitor of nuclear factor κB kinase.

The inhibitor of nuclear factor κB kinase (IKK)-nuclear factor κB (NFκB) pathway is one of the most important cellular signal transduction pathways. It can be activated by diverse stimuli, resulting in liberation of cytoplasmic NFκB from inhibition by inhibitors of NFκB (IκB) after IκB are phosphorylated by IKKβ and IKKα via the canonical and non-canonical pathways, respectively. Activated NFκB then translocates into the nucleus to regulate various NFκB target genes. Through regulation of its target genes, NFκB can regulate various physiologic processes such as cell proliferation, migration and survival. More importantly, activation of the IKK-NFκB pathway has been implicated in carcinogenesis, tumor development, progression and metastasis, and cancer resistance to radiotherapy and chemotherapy. Therefore, molecularly targeted inhibition of the different components of this pathway has been widely explored for treatment of cancer either alone or in combination with other cancer therapies. A growing body of evidence suggests that IKKβ may be a better cancer treatment target in this pathway, because several novel NFκB-independent functions of IKKβ have been identified recently, including promotion of DNA double strand break repair to increase tumor cell resistance to ionizing radiation and chemotherapy in an apoptosis-independent manner. In this review, we highlight some of these new findings and discuss the therapeutic potential of IKKβ specific inhibitors as a novel tumor sensitizer.