**4. Conclusion and future directions**

In summary, this chapter highlights a significant role of NF-ĸB phosphorylation in driving the initiation and progression of several cancers as well as chemoresistance to first-line therapies. Furthermore, we emphasized the relationship between p65 phosphorylation and the role that constitutively active kinases play in promoting the cancer phenotype, via utilization of ATP as the phosphate donor. Finally, we underlined the well-established therapeutic potential of targeting these kinases in the treatment of various cancers. Despite these encouraging data, we acknowledge that the difficulties with drug resistance and toxicity continue to present critical challenges for the use of kinase inhibitors in both clinical and experimental oncology. Furthermore, issues related to the inadequate understanding of the selectivity of the kinase inhibitors have also plagued the successful clinical utility of these inhibitors. Nevertheless, a key challenge for overcoming this enigma is to identify the most efficacious, complementary, and least toxic combinations of kinase inhibitors for targeted cancer treatment [97, 98]. This will likely lead to the development of multimodal treatment initiatives that evade the treatment-related drug resistance. Finally, it is well known that cancers have heterogeneous populations of cells, and these may differentially contribute to chemoresistance [99, 100]. To address this, many efforts are underway to eliminate cancer stem cells as main culprits of this intrinsic heterogeneity, which will undoubtedly improve our understanding of better drug design and efficiency [101, 102].
