Deregulated Receptor Tyrosine Kinases

Receptor protein tyrosine kinases (RPTKs) are a subclass of transmembrane-spanning proteins with ligand-stimulatable kinase activity. These enzymes are important regulators of intracellular signal transduction pathways involved in a number of cell functions, such as cell differentiation and proliferation. The activation of these kinases by their cognate ligands involves a complex and multistep process. Binding of the growth factor to the extracellular domain of the protein results in receptor dimerization and subsequent autotransphosphorylation of each intracellular domain at specific tyrosine residues.278 The phosphorylated tyrosine residues act as docking sites for protein adaptors that initiate a cascade of intracellular biological events.279 The activity of RPTK is tightly controlled under normal physiological conditions,280 but many different tumor types have been shown to have dysfunctional RPTKs as a consequence of mutations or genetic alterations. Irrespective of the cause, this leads to enhanced or constitutive kinase activity and, in turn, to aberrant and inappropriate post receptor cellular signaling within the tumor cell. The RPTKs involved in oncogenic transformation and the intracellular components of the pathways initiated by these receptors have become attractive targets for cancer drug discovery programs, and many efforts have focused in the last few years on preventing receptor activation or blocking deregulated signal transduction pathways (see 7.08 Kinase Inhibitors for Cancer). Two representative examples of deregulated receptor tyrosine kinases in cancer cells are given below.

7.01.8.1.1 Epidermal growth factor receptors

The EGF family of type I receptor tyrosine kinases comprises four structurally related proteins: EGFR (erbB-1, HER1); erbB-2 (HER2, Neu), erbB-3 (HER3), and erbB-4 (HER4). The biological activities of these transmembrane proteins are intimately interrelated, and their activation by a broad spectrum of growth factors (e.g., EGF, TGF-a amphiregulin, betacellulin, heparin-binding EGF, and, epiregulin) triggers the initiation of signal transduction pathways that in the main result in cellular proliferation, apoptosis, differentiation, angiogenesis, motility, and invasion. This family of receptors was first implicated in cancer when the avian erythroblastosis tumor virus was found to encode an aberrant form of the human EGFR. Additional studies have supported an important role for this family of RTKs in the development and progression of numerous human tumors. Overexpression of EGFR or coexpression of both receptor and ligand(s) is a frequent event in a large variety of epithelial cancers and is associated with advanced disease and poor prognosis. In a significant proportion of these tumors, gene amplification is accompanied by rearrangements that result in constitutively active receptors. Thus, overexpression of erbB-2 occurs in around 30% of breast cancers281 and coexpression of elevated levels of EGFR and erbB-2 has been observed in ovarian cancer patients. Interestingly, although erbB-2 is an orphan receptor, it participates in EGF receptor signaling by heterodimerization with other members of this receptor family. Dimerization causes activation of the kinase domain, leading to initiation of signal transduction pathways linked to cell survival and division. Constitutive activation has also been observed in mutated forms of the EGFR. The most common mutation (EGFRvIII), which is found in gliomas, NSCLC, and breast cancer, lacks domains I and II of the extracellular domain, and, despite being unable to bind to the ligands, displays constitutive kinase activity.

7.01.8.1.2 Oncogenic activation of c-Kit

The proto-oncogenic c-Kit receptor responds specifically to its physiological ligand, the stem cell factor (SCF), but its activation in tumor cells can proceed by alternative mechanisms. Thus, more than 30 gain-of-function mutations in the extracellular dimerization domain, the intracellular juxtamembrane domain, and the kinase domain have been identified in the c-Kit receptor.282'283 The transforming mechanism of these mutations (single or multiple amino acid changes) involves dimer formation resulting in constitutive SCF-independent kinase activation.

Upregulation of the kinase activity of c-Kit by somatic mutations has been documented in a number of human malignancies, particularly in gastrointestinal stromal tumors (GISTs) (around 85-90% of all diagnosed cases). The constitutive c-Kit kinase activity observed in GISTs was hypothesized to be crucial to the pathogenesis of this disease,284,285 and this premise has been recently confirmed with the objective responses observed with c-Kit kinase inhibitors (e.g., imatinib) in GISTs clinical trails.286 Thus, clinical responses in GIST patients following treatment with imatinib appear to be associated with the presence of activating mutations of c-Kit, as patients expressing wild-type c-Kit, had a significantly lower response.

In addition to GISTs, activation of the kinase activity of c-Kit by somatic mutations has been documented in seminoma, acute myelogenous leukaemia, and mastocytosis, and paracrine or autocrine activation of this receptor has also been postulated for SCLC and ovarian cancer.

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