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Tyrosine kinase - Role and significance in Cancer.

Tyrosine kinases are important mediators of the signaling cascade, determining key roles in diverse biological processes like growth, differentiation, metabolism and apoptosis in response to external and internal stimuli. Recent advances have implicated the role of tyrosine kinases in the pathophysiology of cancer. Though their activity is tightly regulated in normal cells, they may acquire transforming functions due to mutation(s), overexpression and autocrine paracrine stimulation, leading to malignancy. Constitutive oncogenic activation in cancer cells can be blocked by selective tyrosine kinase inhibitors and thus considered as a promising approach for innovative genome based therapeutics. The modes of oncogenic activation and the different approaches for tyrosine kinase inhibition, like small molecule inhibitors, monoclonal antibodies, heat shock proteins, immunoconjugates, antisense and peptide drugs are reviewed in light of the important molecules. As angiogenesis is a major event in cancer growth and proliferation, tyrosine kinase inhibitors as a target for anti-angiogenesis can be aptly applied as a new mode of cancer therapy. The review concludes with a discussion on the application of modern techniques and knowledge of the kinome as means to gear up the tyrosine kinase drug discovery process.


Introduction
Multicellular organisms live in a complex milieu where signaling pathways contribute to critical links, for their existence. Tyrosine kinases are important mediators of this signal transduction process, leading to cell proliferation, differentiation, migration, metabolism and programmed cell death. Tyrosine kinases are a family of enzymes, which catalyzes phosphorylation of select tyrosine residues in target proteins, using ATP. This covalent post-translational modification is a pivotal component of normal cellular communication and maintenance of homeostasis [1,2]. Tyrosine kinases are implicated in several steps of neoplastic development and progression. Tyrosine kinase signaling pathways normally prevent deregulated proliferation or contribute to sensitivity towards apoptotic stimuli. These signaling pathways are often genetically or epigenetically altered in cancer cells to impart a selection advantage to the cancer cells. Thus, it is no wonder that aberrant enhanced signaling emanating from tyrosine kinase endows these enzymes a dominating oncoprotein status, resulting in the malfunctioning of signaling network [3].
The discovery that SRC oncogene having a transforming non receptor tyrosine kinase activity [4], and the finding of EGFR, the first receptor tyrosine kinase paved the way to the understanding of the role and significance of tyrosine kinase in cancer [5]. With the deciphering of the Human Genome Project more than 90 tyrosine kinases have been found out. The more science entangles the intricacies of cellular signaling the more we find the involvement of tyrosine kinase in cellular signaling circuits that are implicated in cancer development. Tyrosine kinases represent a major portion of all oncoprotein that play a transforming role in a plethora of cancers. Hence the identification and development of therapeutic agents for disease states that are linked to abnormal activation of tyrosine kinases due to enhanced expression, mutation or autocrine stimulation leading to abnormal downstream oncogenic signaling have taken a centre stage as a potent target for cancer therapy [6,7].

Biochemical mechanism of action of tyrosine kinase
Tyrosine kinases are enzymes that selectively phosphorylates tyrosine residue in different substrates. Receptor tyrosine kinases are activated by ligand binding to their extracellular domain. Ligands are extracellular signal molecules (e.g. EGF, PDGF etc) that induce receptor dimerization (except Insulin receptor). Different ligands employ different strategies by which they achieve the stable dimeric conformation. One ligand may bind with two receptor molecules to form 1:2 ligand: receptor complex e.g. growth hormone and growth hormone receptor, while in other cases two ligands binds simultaneously to two receptors 2:2 ligand receptor complex and provides the simplest mechanism of receptor dimerization e.g. VEGF and VEGFR. The receptor dimerization is also stabilized by receptorreceptor interactions. Some ligand receptor is not sufficient for some complex and is stabilized by accessory molecules e.g. FGFs are unable to activate FGFR complex and is stabilized by heparin sulfate proteoglycans (HSPG). Ligand binding to the extracellular domain stabilizes the formation of active dimmers and consequently protein tyrosine kinase activation.
Structural studies of the catalytic core of several RTKs, supported by biochemical and kinetic studies of receptor phosphorylation have provided proof that receptor oligomerization increases the local concentration of the RTKs, leading to efficient transphosphorylation of tyrosine residues in the activation loop of the catalytic domain. Upon tyrosine phosphorylation the activation loop adopts an open conformation that gives access to ATP and substrates and makes ATP transfer from Mg-ATP to tyrosine residue on the receptor itself and on cellular proteins involved in signal transduction.
The ATP binding intracellular catalytic domain that catalyzes receptor autophosphorylation displays the highest level of conservation between the RTKs. The ATP binding site serves as a docking site for specific binding of cytoplasmic signaling proteins containing Src homology-2 (SH2) and protein tyrosine binding (PTB) domains. These proteins in turn recruit additional effector molecules having SH2, SH3, PTB and Pleckstrin homology (PH) domain. This results in the assembly of signaling complexes to the activated receptor and the membrane and subsequent activation of a cascade of intracellular biochemical signals, which leads to the activation or repression of various subsets of genes and thus defines the biological response to signals. During these processes, receptors migrate within the plasma membrane and are internalized through clathrin-coated invagination, which eventually seal off and forms an endocytic vesicle. The endocytic vesicles fuse with the lysosomes and in the process the receptor and ligand may be degraded by the lysosomal enzymes. The receptors are also recycled in some cases. During the whole process of receptor internalization the ligand receptor complex is dissociated and this results in the termination of the signaling reaction. Figure 1. Schematic representation of the mode of action of tyrosine kinase. PK represents protein kinase and PP stands for protein phosphatase.

Classification
Tyrosine kinases are primarily classified as receptor tyrosine kinase (RTK) e.g. EGFR, PDGFR, FGFR and the IR and non-receptor tyrosine kinase (NRTK) e.g. SRC, ABL, FAK and Janus kinase. The receptor tyrosine kinases are not only cell surface transmembrane receptors, but are also enzymes having kinase activity. The structural organization of the receptor tyrosine kinase exhibits a multidomain extracellular ligand for conveying ligand specificity, a single pass transmembrane hydrophobic helix and a cytoplasmic portion containing a tyrosine kinase domain. The kinase domain has regulatory sequence both on the N and C terminal end [2,8].
NRTK are cytoplasmic proteins, exhibiting considerable structural variability. The NRTK have a kinase domain and often possess several additional signaling or protein-protein interacting domains such as SH2, SH3 and the PH domain [9]. The tyrosine kinase domain spans approximately 300 residues and consists of an N terminal lobe comprising of a 5 stranded β sheet and one α helix, while the C terminal domain is a large cytoplasmic domain that is mainly α helical. ATP binds in the cleft in between the two lobes and the tyrosine containing sequence of the protein substrate interacts with the residues of the C terminal lobe. RTK are activated by ligand binding to the extracellular domain followed by dimerization of receptors, facilitating trans-phosphorylation in the cytoplasmic domain whereas the activation mechanism of NRTK is more complex, involving heterologous protein-protein interaction to enable transphosphorylation [10].

Oncogenic activation of tyrosine kinase
Normally the level of cellular tyrosine kinase phosphorylation is tightly controlled by the antagonizing effect of tyrosine kinase and tyrosine phosphatases. There are several mechanisms by which tyrosine kinase might acquire transforming functions, but the ultimate result is the constitutive activation of normally controlled pathways leading to the activation of other signaling proteins and secondary messengers which serves to hamper the regulatory functions in cellular responses like cell division, growth and cell death [11]. Constitutive activation of tyrosine kinase may occur by several mechanisms.

Activation by mutation
An important mechanism leading to tyrosine kinase deregulation is mutation. Mutations within the extracellular domain e.g. EGFRv III mutant lacks amino acid 6-273 which gives rise to receptor tyrosine kinase constitutive activity, that leads to cell proliferation in the absence of ligand in glioblastomas, ovarian tumors and non small cell lung carcinoma [12]. Point mutations either in the extracellular domain of the FGFR 3 results in an unpaired cysteine residue allowing abnormal receptor dimerization through intermolecular disulfide bonding, or in the activation loop of kinase domain were identified in multiple myeloma. Somatic mutations in the EGFR 2 and 3 have been associated with human bladder and cervical carcinomas. Breakpoints of abnormal chromosomal translocation are also an important source of mutation [13]. gene product has a tyrosine kinase activity several fold higher than it's normal counterpart and correlates with the disease phenotype [14,15,16,17,18].

TEL-ABL and human leukemia
TEL-ABL tyrosine kinase like ABL-BCR is constitutively phosphorylated due to reciprocal translocation t (9,12) in case of ALL and with a complex karyotype t (9,12,14) in patients with CML. TEL which is a putative transcription factor is fused in-frame with exon-2 of the ABL proto-oncogene, producing a fusion protein product with elevated tyrosine kinase activity [14,19]. Other important translocations include t (5,12) in CMML producing TEL-PDGF receptor. The helix-loop-helix motif of TEL is believed to induce homodimerization and kinase activation of the TEL-ABL and TEL-PDGFRβ fusion proteins. NPM-ALK fusion products t(2,5) is constitutively activated in Anaplastic large cell lymphoma [20,21].

Autocrine-Paracrine loops
Autocrine-paracrine stimulation serves as an important mechanism for the constitutive activation of tyrosine kinase specially receptor tyrosine kinases. This activation loop is stimulated when a receptor tyrosine kinase is abnormally expressed or overexpressed in presence of it's associated ligand or when there is an overexpression of the ligand in presence of it's cognate receptor. A role of autocrineparacrine stimulation has been immanent in a variety of human cancers. Burning examples are being provided by EGFR, PDGFR and IGF receptors and their associated ligands [22].

EGFR in autocrine paracrine loops
Strong associations have been studied among the expression of EGFR and it's primary ligand EGF and TGFα in many human cancers including non small cell lung cancer [22], bladder cancer, breast cancer and glioblastoma multiforme. Increased expression of EGFR is reported in 40-80% of non small cell lung cancer and is also overexpressed in 50% of primary lung cancer [15]. TGFα another ligand of EGFR is also involved in autocrine paracrine growth loops in 20-40% of lung cancer [23]. EGFR overexpression of wild type or mutated forms is documented in 40% of cases of glioblastoma multiforme [24] and 40%-50 % of bladder cancer patient [25].

PDGFR in Autocrine paracrine Loop
Concurrent expression of PDGFR and it's cognate ligand PDGF-A and PDGF-B has been observed in most astrocytic brain tumors and gliomas [26].

Insulin like growth factor receptors in Autocrine growth loop
Coexpression of IGFR and its ligand IGF I and IGF II is reported in the pathogenesis of breast cancer, prostrate cancer and small cell lung cancer [27]. Elevated IGF-I R autophosphorylation and kinase activity has been reported in breast cancer [28]. Elevated prostrate cancer risk is also correlated with elevated plasma IGF-I levels [29]. Hence a strong association of autocrine paracrine loops has been implicated in the pathogenesis of several cancers.

Tyrosine kinases as targets for anticancer agents
The role of tyrosine kinases in cancer molecular pathogenesis is immense and recently kinases have come in vogue as potential anticancer drug targets, as a result a couple of anticancer drugs are in the market. The complexity and the number of tyrosine kinases have greatly increased with the sequencing effort of the Human Genome Project, thus providing more opportunities for drug discovery. Recent understanding of the molecular pathophysiology of cancer have highlighted that many tyrosine kinases are found upstream or downstream of epidemiologically relevant oncogenes or tumor suppressor, in particular the receptor tyrosine kinases [30].

Site of targeting
Cancer research got a boom with the declaration by the US president Richard Nixon in The National Cancer Act (1971). By the late 1980 there were evidence of low molecular weight tyrosine kinase inhibitors. Inhibiting the activity of tyrosine kinases by low molecular weight compounds capable of interfering with either ligand binding (in the case of receptor tyrosine kinases) [31] or with protein substrate (in case of non receptor tyrosine kinase) has proved to be difficult [32]. Although the bisubstrate inhibitor approach offered promise, but with very little practical progress. Approaches to generate non-competitive or allosteric inhibitors have also failed. The ATP competitive inhibitors appear to be the target of choice [33].

5.2.
The ATP binding site ATP binds within a deep cleft formed between the two lobes of the tyrosine kinase domain. Though the ATP binding site is highly conserved the architecture in the regions proximal to the ATP binding site does afford some key diversity for designing new drug and has potential application in drug discovery. The ATP binding sites have the following features- Proliferation Gene tra nscription P P P P P P P P a) Adenine region -contains two key Hydrogen bonds formed by the interaction of N-1 and N-6 amino group of the adenine ring. Many potent inhibitors use one of these Hydrogen bonds. b) Sugar region -a hydrophilic region, except a few e.g. EGFR. Hydrophobic pocket -though not used by ATP but plays an important role in inhibitor selectivity. c) Hydrophobic channel -not used by ATP and may be exploited for inhibitor specificity. d) Phosphate binding region -can be used for improving inhibitor selectivity [34].

Small molecule inhibitor
Tyrosine kinase forms a significant share of all oncoproteins thus they take centre stage as possible targets for cancer therapy. Hence low molecular weight tyrosine phosphorylation inhibitors (tyrphostins) have been proposed to be prospective anti-proliferating agents. By late 1980s it was proved that low molecular weight EGFR inhibitors could block EGF dependent cell proliferation [35]. Within a short time reports concerning effective tyrosine kinase inhibitors was the key promising development in anticancer development. With further research in the following years it was quite clear that neglected kinase targets against the biases have come into vogue [36]. Most of the tyrosine kinase inhibitors generated since have been ATP mimics. Interestingly many tyrphostins that possess one aromatic ring are substrate mimics [37]. These substrate mimics can be interestingly converted into ATP mimics once the nitrogen of the characteristic benzene malonitrile is incorporated into the second ring. Compounds that are found to be ATP mimics possess at least two aromatic rings. The ATP binding site though evolutionarily conserved can be selectively targeted by taking advantage of the minor difference in the kinase domain. The minor difference leads to changes in hydrogen bonding and hydrophobic interactions resulting in differences of affinity [38].
Of all the tyrosine kinase inhibitors the most successful are Gleevec, Iressa and Tarceva. The novel anticancer drug Gleevec/ Glivec/ Imatinib mesylate (Novartis STI571) is a success for CML and c-kit positive metastatic GIST. Gleevec selectively and effectively inhibits the kinase activity of BCR-ABL fusion protein, which is responsible for the constitutive proliferative signaling. It also inhibits TEL- cleft and with peptide segments just outside the cleft. A large change in conformation of the nucleotide binding domain is accompanied with the binding of the drug. The binding of STI571 prevents ATP to access the ATP binding cleft and thus inhibits subsequent tyrosine phosphorylation of the substrate [34,36,39]. Iressa is a selective inhibitor of EGF receptor tyrosine kinase in non small cell lung cancer and squamous cell carcinoma [40].
The downstream target of PI3K pathway, mTOR (non receptor tyrosine kinase) responsible for abnormal cellular growth and proliferation in glioblastoma and renal cancer is inhibited by rapamycin and CCI779. These two compounds are currently in phase II studies [41].

Monoclonal antibody
The extracellular domain of the receptor tyrosine kinase provides an excellent target for monoclonal antibodies. With the advancement of genomics, design, selection and production of therapeutic monoclonal antibodies has become much more easier. The revolution in antibody technology now allows us to produce humanized, human chimeric or bispecific antibody for targeted cancer therapy [31,42].
The EGFR family of receptor tyrosine kinase comprises of four members -the EGFR/ Erb B1, HER-2/ Erb B2, HER-3/ Erb B3 and HER-4/ Erb B4. Members of the EGFR family are involved in some complex biological signal transduction network. Both EGFR and HER-2/ neu are amplified in tumor samples of breast, lung and colorectal tissues. Their overexpression leads to elevated MAP kinase and PI3 kinase recruitment and subsequent suppression of apoptosis, deregulation of cell cycle and proliferation.
Based on the discovery of the importance of HER-2 gene amplification in breast cancer Herceptin (Transtuzumab) was developed by Genetech in 1988 and is one of the best examples of targetted next generation anticancer therapeutic for cancer. Tyrosine kinases are key regulators of cell survival and proliferation in breast cancer [42,43]. The orphan receptor tyrosine kinase HER2 gene is amplified in breast cancer and acts as a major signaling partner for other EGFR family members leading to proliferation, differentiation, antiapoptosis [44] and tumor progression [45]. Herceptin was the first genome based targeted anticancer therapeutic, approved by FDA in 1998. Binding of Herceptin to HER receptor leads to receptor internalization, inhibition of cell cycle progression and antibody dependent cellular toxicity or eliciting the immune response. Herceptin induces normalization and regression of angiogenesis in HER-2 overexpressing breast cancer [46] and even blocks cleavage of HER2, which generates a membrane-bound constitutively active truncated receptor. Rituximab is an anti CD20 antibody, effective against Non Hodkins Lymphoma [47].
EFGR is also overexpresed in many cancers especially in breast cancer. EGFR over amplification also leads to suppression of apoptosis. Proliferation, migration, stromal cell invasion and neovascularization. Important anti-EGFR monoclonal antibodies are C225 by Imclone and 2C4 by Genetech and Osidem by Mederex. C225 or cetuximab is targeted against EGFR/ Erb B1 while 2C4 is targeted against HER-2/ Erb B2 member of the EGFR family. Angiogenesis, the formation of new blood vessels to the tumor site is mainly induced and regulated by VEGF. Blocking angiogenesis is now considered to be a promising approach for anticancer therapy and the use of anti-VEGF MAb has demonstrated tumor suppression.
Certain antigens are overexpressed in cancers. P12 antigen overexpression is associated with a wide range of cancer cell lines and tissues and antibody directed towards these antigens may serve as important contributors to cancer therapeutics as exemplified by the results of priliminary trials. MAb P12 reacts with the carbohydrate sequence present on high molecular weight glycoproteins. Oncologists are now interested in newer MAbs as promising agents for the treatment of cancer.

Hsp 90 and other novel strategies
Heat shock proteins (Hsp-s) are ubiquitous proteins known for the maintenance of cellular homeostasis and are inducible under variety of stresses. Hsp-s are mainly involved in the proper folding of other proteins and hence referred to as molecular chaperons [48,49]. The accumulation of Hsp-s is seen in pathological conditions and tumors. Most kinases require molecular chaperons to maintain their activation competent conformation. Hsp-s interacts with and stabilizes various kinases [50]. Chaperon based inhibitors other than interacting with protein kinases, prevent the associated chaperon(s) from maintaining the activation competent conformation of the kinase. The result being the proteosomal degradation of the misfolded kinases, thus diminishing the level of many kinases. The Hsp-s has an unique ATP binding site, including a Bergerat fold characteristic of bacterial gyrase, topoisomerases and histidine kinases. Thus the ATP binding site serves as a robust antitumor target for kinase related chaperone machinery. Important examples are Geldanamycin, Cisplatin, Novobiocin, Radicol and other purine based inhibitors. Geldanamycin affects ErbB2, EGF, v-Src, Raf-1 etc [51,52].

Antibody drug conjugate
Frontline therapy being scarcely full proof, hence there is a resurgent trend towards immunotherapy. The efficacy of the antibodies that targets specific molecules expressed by tumor cells can be increased by attaching toxins to them [53]. Existing immunotoxins are based on bacterial toxins like pseudomonas exotoxin, plant exotoxin like ricin or radio-nucleotides. The toxins are chemically conjugated to a specific ligand such as the variable domain of the heavy or light chain of the monoclonal antibody. Normal cells lacking the cancer specific antigens are not targeted by the targeted antibody [54]. The most promising immunotoxin is the EGF fusion protein DAB 389 EGF, which is a fused EGF specific sequence and diphtheria toxin and have been found to be effective in EGFR over expressing breast tumor and non small cell lung cancer. The use of therapeutic antibody for the development of antibody-drug conjugate has been tried to improve the therapeutic potential e.g. Tositumomab by GlaxoSmithcline [55], Anti-Tac(Fv)-PE38(LMB-2) against CD25, in B, T cell lymphoma and anti-B4-bR against CD19 in B-Non Hodgkins lymphoma [56]. As molecular studies of cancer have started revealing an increased epitope repertoire due to great strides in genomics and proteomics, the search for more effective Antibody-drug conjugate has got a spur in recent times [57].

Antisense strategies and peptide drugs
Antisense are small pieces of synthetic oligonucleotides that are designed to interact with the mRNA by Watson-Crick base pairing to block the transcription and thus translation of target proteins. Antisense oligodeoxynucleotides (ODN) targeting IGF-1R induces apoptosis in malignant melanoma and is also effective in breast cancer [58].
Protein-protein interaction is very important in cellular processes. Hence peptide and peptidomimetics that interfere with this interaction are important. Grb2 is an essential component in the Ras signaling pathway and it's interaction with Sos is responsible for the down stream signaling process. Proline rich "Peptidimer" having two VPPVPPRRR sequence specifically recognizes Grb2 and selectively blocks Grb2-Sos interaction an important step in EGFR over expressing cancers [31]. Small peptides mAZpTyr-(α-Me)pTyr-Asn-NH 2 [58] and peptidomimetics like AHNP anti erbB2 are even known to inhibit unwanted tyrosine kinase dimerization by competing with target proteins thus the peptides or peptidomimetics acts as antagonist of receptor tyrosine kinase [59,60].

Inhibitors of Angiogenesis
Tumor cell transformation is a multistage process. An insitu tumor after a period of time abruptly sparks the formation of new blood vessels from the preexisting vasculature a process termed as angiogenesis or neovascularization. Tyrosine kinase plays an important role in this process [61]. This process though occurs normally during embryonic development, female reproductive cycle or wound healing is found as a crucial step in tumor transition from benign to malignant form, capable of spreading throughout the body [61,62,63].
VEGF (Flt-1) receptor tyrosine kinase mediated mitogenesis of human endothelial cells and growth of multiple tumor types is inhibited by SU5416 [64]. PD173074 is a potent inhibitor of FGFR1 and also VEGFR2 [65]. PD98059 is an important inhibitor of MAPK cascade that lies downstream of Ras pathway and thus is effective in many tumors [66]. Antiangiogenic drugs stops new vessels from forming around a tumor and break up the existing network of abnormal capillaries that feeds the cancerous mass, thus shrinks the tumor by limiting blood supply. Treatment of cancer faces the main fear of acquired drug resistance but antiangiogenic therapy does not induce acquired drug resistance and hence can prove valuable for long-term maintenance therapy [67].

Mining the kinome to meet the future challenges
Cancer arises by clonal proliferation from a cell, which builds up a series of mutations leading to abnormal signaling [68]. The Achilles' heel lies in that the cancer cell depends highly on these oncogenic mutations and is said to be "oncogene addicted" [69,70]. With over 500 kinases in the human kinome and as many as 200-300 protein kinases mediating a large number of pathways in a cell at a particular time, selectivity becomes very important considering the cost of drug development. Hence strategies to move kinase drug discovery in a more rapid, comprehensive and efficient manner, including tyrosine kinase target validation, selectivity and drugability are the demand of time [71]. Biochemical, cell based assay and screening methods for the through profiling of the kinase inhibitors using monoclonal antibody based multi-immunoblotting, fluorescent polarization assays, nonradioactive high throughput assays, 2-D NMR approaches should be exploited. Structure based drug design (SBDD) strategies depending on bioinformatics, computational approaches, mathematical models of tumor and normal tissue response, highthroughput X-ray crystallography and chemogenomic approaches can be used to advance molecules through the routine drug discovery process. The use of recent strides in RNA interferance (RNAi) appears to be a promising approach for silencing gene expression, thus elucidating genetics of human disease with emphasis into the biological role of the kinase signaling pathways [72,73]. The promising progress made by the drugs Gleevec, Iressa and Herceptin has brought to light the potential of new innovative genome based molecular therapeutics [74]

Conclusion
The role of tyrosine kinase in the control of cellular growth and differentiation is central to all organisms and has been found to participate in human neoplastic diseases. Tyrosine kinase inhibitors and their potential in clinical application are well documented by dramatic examples like, Gleevec, Iressa and Herceptin. Several tyrosine kinase inhibitors are undergoing human trials and several are in the pipeline of drug discovery. The activities of these drugs are restricted to cancers with alterations in kinase targets, hence broad application of this treatment strategy are challenging. The quick selection of epidemiologically relevant, drugable tyrosine kinase targets coupled to efficient lead finding and optimization needs more intervention in the area of highthroughput cancer genome based molecular therapeutics. All these concerted effort may pave the silverlining to tailor made personalised cancer therapeutics.