**3.3 Cutting edge therapeutics for treating cancers with constitutively active kinases**

Since the mid-1970s, numerous studies have highlighted a crucial role for kinases in promoting tumorigenesis and metastasis [63–67]. This is of no surprise, since a clear majority of protein kinases promote critical cellular functions pertinent to cancer progression, including cell proliferation, survival, and migration [68–72]. Hence, targeting mutated, overexpressed, or hyperactive kinases represents an important and promising clinical niche for developing drugs for cancer therapy [67, 73, 74]. Interestingly, inhibitors against kinases account for approximately 25% of all current drug discovery efforts. So far, ~37 inhibitors with activity targeted to one or multiple kinases have been approved for clinical use [67, 75]. These range from highly selective monoclonal antibodies to more broad-spectrum synthetic or natural small molecules that have achieved a significant increase in patient survival rate in cancers [67]. For example, treatment with imatinib and dasatinib, which are highly potent and selective tyrosine kinase inhibitors against BCR-ABL, produces more favorable outcomes compared to conventional cytotoxic therapy for patients with chronic myeloid leukemia (CML) [76–78]. Similarly, broad-spectrum inhibitors have also been used with great success. For example, CHIR-258, which targets multiple kinases, inhibits VEGFR, platelet-derived growth factor receptor (PDGFR), FMS-like tyrosine kinase-3 (FLT-3), mast/stem cell growth factor receptor (c-Kit), and fibroblast growth factor receptor (FGFR) in multiple myeloma patients and is most effective for killing tumors harboring the translocation t [4, 14] (p16.3;q32.3) with increased expression and activating mutations of FGFR3 [79–81].

Some other major inhibitors to enter the market include those targeting key oncogenic kinase drug targets such as ERBB2 (e.g., afatinib), HER2 (e.g., trastuzumab), and VEGFRs (e.g., sorafenib, a small molecule inhibitor used for the treatment of renal cell, liver. and thyroid cancers) [82–87]. Another successful targeting strategy has been the use of a monoclonal antibody against VEGFR (bevacizumab). Bevacizumab is used in combination with chemotherapy to treat patients with metastatic colon cancer, and its widespread use has resulted in significant improvement in survival outcomes [88]. Other examples include inhibitors against Kit, PDGFRs, proto-oncogene tyrosine-protein kinase Src (SRC), mechanistic target of rapamycin and FK506-binding protein 12-rapamycin-associated protein 1 (mTOR), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), serine/threonine-protein kinase B (PKB or Akt)—Raf (BRAF), and epidermal growth factor receptor (EGFR) (e.g., cetuximab, panitumumab), all of which act to activate significant tumor cell signaling pathways such as NF-ĸB [67, 89]. For instance, several FDA-approved kinase inhibitors, although not perceived as direct NF-ĸB inhibitors, have been shown to suppress NF-κB signaling [89]. These include inhibitors targeting EGFR in breast and lung cancer, Akt in breast cancer, GSK-3β in pancreatic cancer, NIK in melanoma, BRAF in multiple myeloma, and IKK in brain and liver cancer [89–91]. Specifically, GSK2118436, PLX4720, sorafenib, and PLX4032 are all drugs which are currently being used to target B-RafV600E in advanced cancers with elevated NF-ĸB activity [73, 92–94]. Finally, small molecule inhibitors targeting Akt, which include perifosine, GSK690693, VQD002, and MK2206, are also being tested clinically [95, 96].

**55**

*Phosphorylation of NF-κB in Cancer*

patient clinical outcomes.

*DOI: http://dx.doi.org/10.5772/intechopen.83650*

**4. Conclusion and future directions**

better drug design and efficiency [101, 102].

**Acknowledgements**

In summary, these studies highlight the importance of inhibition of distinct kinase signaling pathways as a means of minimizing cytotoxic effects on noncancerous cells, thus bestowing selective killing of tumor cells and improving

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

This publication is made possible, in part, with support from the Indiana Clinical and Translational Sciences Institute (CTSI) funded from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (to TL); V foundation Kay Yow Cancer Fund (Grant 4486242 to TL); NIH-NIGMS Grant (#1R01GM120156-01A1 (to TL); and 100 VOH Grant (#2987613 to TL), as well as NIH-NCI Grant (#1R03CA223906-01). *Adenosine Triphosphate in Health and Disease*

tory disease.

**kinases**

mutations of FGFR3 [79–81].

of tumor tissues. It will be critical to develop new compounds that circumvent acquired resistance to the first-generation kinase inhibitors for patients with refrac-

**3.3 Cutting edge therapeutics for treating cancers with constitutively active** 

Since the mid-1970s, numerous studies have highlighted a crucial role for kinases in promoting tumorigenesis and metastasis [63–67]. This is of no surprise, since a clear majority of protein kinases promote critical cellular functions pertinent to cancer progression, including cell proliferation, survival, and migration [68–72]. Hence, targeting mutated, overexpressed, or hyperactive kinases represents an important and promising clinical niche for developing drugs for cancer therapy [67, 73, 74]. Interestingly, inhibitors against kinases account for approximately 25% of all current drug discovery efforts. So far, ~37 inhibitors with activity targeted to one or multiple kinases have been approved for clinical use [67, 75]. These range from highly selective monoclonal antibodies to more broad-spectrum synthetic or natural small molecules that have achieved a significant increase in patient survival rate in cancers [67]. For example, treatment with imatinib and dasatinib, which are highly potent and selective tyrosine kinase inhibitors against BCR-ABL, produces more favorable outcomes compared to conventional cytotoxic therapy for patients with chronic myeloid leukemia (CML) [76–78]. Similarly, broad-spectrum inhibitors have also been used with great success. For example, CHIR-258, which targets multiple kinases, inhibits VEGFR, platelet-derived growth factor receptor (PDGFR), FMS-like tyrosine kinase-3 (FLT-3), mast/stem cell growth factor receptor (c-Kit), and fibroblast growth factor receptor (FGFR) in multiple myeloma patients and is most effective for killing tumors harboring the translocation t [4, 14] (p16.3;q32.3) with increased expression and activating

Some other major inhibitors to enter the market include those targeting key oncogenic kinase drug targets such as ERBB2 (e.g., afatinib), HER2 (e.g., trastuzumab), and VEGFRs (e.g., sorafenib, a small molecule inhibitor used for the treatment of renal cell, liver. and thyroid cancers) [82–87]. Another successful targeting strategy has been the use of a monoclonal antibody against VEGFR (bevacizumab). Bevacizumab is used in combination with chemotherapy to treat patients with metastatic colon cancer, and its widespread use has resulted in significant improvement in survival outcomes [88]. Other examples include inhibitors against Kit, PDGFRs, proto-oncogene tyrosine-protein kinase Src (SRC), mechanistic target of rapamycin and FK506-binding protein 12-rapamycin-associated protein 1 (mTOR), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), serine/threonine-protein kinase B (PKB or Akt)—Raf (BRAF), and epidermal growth factor receptor (EGFR) (e.g., cetuximab, panitumumab), all of which act to activate significant tumor cell signaling pathways such as NF-ĸB [67, 89]. For instance, several FDA-approved kinase inhibitors, although not perceived as direct NF-ĸB inhibitors, have been shown to suppress NF-κB signaling [89]. These include inhibitors targeting EGFR in breast and lung cancer, Akt in breast cancer, GSK-3β in pancreatic cancer, NIK in melanoma, BRAF in multiple myeloma, and IKK in brain and liver cancer [89–91]. Specifically, GSK2118436, PLX4720, sorafenib, and PLX4032 are all drugs which are currently being used to target B-RafV600E in advanced cancers with elevated NF-ĸB activity [73, 92–94]. Finally, small molecule inhibitors targeting Akt, which include perifosine, GSK690693, VQD002, and MK2206, are also being tested clinically [95, 96].

**54**

In summary, these studies highlight the importance of inhibition of distinct kinase signaling pathways as a means of minimizing cytotoxic effects on noncancerous cells, thus bestowing selective killing of tumor cells and improving patient clinical outcomes.
