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Home , Autophosphorylation, Binding site, Epidermal growth factor, ErbB, ERBB3, ErbB4

Endocrine-Related (2001) 8 161–173

Receptor signalling as a target for cancer intervention strategies

E Zwick, J Bange and A Ullrich

Max-Planck-Institut fu¨r Biochemie,Department of Molecular Biology,Am Klopferspitz 18A,82152 Martinsried, Germany (Requests for offprints should be addressed to A Ullrich; Email: [email protected])

Abstract In multicellular organisms,communication between individual cells is essential for the regulation and coordination of complex cellular processes such as growth,differentiation,migration and . The plethora of networks mediating these biological processes is regulated in part by polypeptide growth factors that can generate signals by activating cell surface receptors either in paracrine or autocrine manner. The primary mediators of such physiological cell responses are tyrosine (RTKs) that couple binding to downstream signalling cascades and transcription. Investigations over the past 18 years have revealed that RTKs are not only key regulators of normal cellular processes but are also critically involved in the development and progression of . Therefore,signalling pathways controlled by tyrosine kinases offer unique opportunities for pharmacological intervention. The aim of this review is to give a broad overview of RTK signalling involved in tumorigenesis and the possibility of target-selective intervention for anti-cancer therapy. Endocrine-Related Cancer (2001) 8 161–173

Introduction phosphorylated and activated, such as Src and phospholipase Cγ, or adaptor molecules that link RTK activation to On the basis of their structural characteristics, receptor downstream signalling pathways (Pawson 1995). One tyrosine kinases (RTKs) can be divided into 20 subfamilies important adaptor complex is the SHC–Grb2–Sos which share a homologous domain that specifies the catalytic complex that couples RTKs via Ras to the extracellular function (van der Geer et al. 1994). All RTKs regulated kinase (ERK)/-activated protein (MAP) consist of a single transmembrane domain that separates the kinase pathway which is crucial for RTK-induced cell intracellular tyrosine kinase region from the extracellular proliferation (Dhanasekaran & Reddy 1998) (Fig. 1). portion (Ullrich & Schlessinger 1990). The latter exhibit a variety of conserved elements including immunoglobulin (Ig)-like or epidermal (EGF)-like domains, Deregulation of RTKs fibronectin type III repeats or -rich regions that are characteristic for each subfamily of RTKs. Since the first connection between a viral , a The catalytic domain that displays the highest level of mutated RTK and human cancer was made in 1984 (Ullrich conservation includes the ATP- that catalyses et al. 1984), it is well known that aberrant signalling by receptor and tyrosine RTKs is critically involved in human cancer and other of RTK substrates (Yarden & Ullrich 1988). Ligand binding hyper-proliferative diseases. Constitutive activation of RTKs, to the extracellular domain leads to conformational changes which has been shown to be important for malignant that induce and stabilize receptor dimerization leading to transformation and tumour proliferation, can occur by several increased kinase activity and autophosphorylation of tyrosine mechanisms (Kolibaba & Druker 1997). In most cases gene residues (Greenfield et al. 1989, Ullrich & Schlessinger amplification, overexpression or are responsible 1990, Heldin 1995). Phosphorylation of distinct tyrosine for the acquired transforming potential of oncogenic RTKs. residues of the activated receptor creates binding sites for Somatic and germline mutations, which are associated with Src homology 2 (SH2)- and phosphotyrosine binding (PTB) distinct inherited and spontaneous human cancer syndromes, domain-containing . Molecules recruited via these have been observed in at least ten different RTK families binding motifs are either that are tyrosine (Robertson et al. 2000). These alterations include deletion or

Endocrine-Related Cancer (2001) 8 000–000 Online version via http://www.endocrinology.org 1351-0088/01/008–000  2001 Society for Endocrinology Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 02:58:10PM via free access Zwick et al.: RTKs in anti-cancer strategies

Figure 1 Target-selective intervention of RTK signalling. Important signalling pathways induced by RTKs and a summary of the most successful strategies towards the prevention and interception of RTK signalling. Abbreviations: ERK, extracellular-regulated kinase; JNK,c-Jun terminal kinase; PI3 kinase,phosphatidylinositol-3 kinase; PLC γ, γ.

within the extracellular region or alterations of the expressed or overexpressed in the presence of its cognate catalytic domain, especially of the ATP-binding motif, which ligand, or when overexpression of the ligand occurs in the all result in a constitutive active RTK. In addition, mutations presence of its associated receptor. In many solid tumours it within the transmembrane domain have been shown to lead has been shown that elevated levels of both growth factor to ligand-independent kinase activation as reported for the receptor and its ligand are expressed concomitantly (Salomon RTK HER2/neu. et al. 1995). Activation of autocrine growth factor loops is another mechanism of aberrant RTK signalling and has been Intervention strategies frequently described for the epidermal (EGFR) and -like growth factor-I receptor (IGF-IR) Increasing knowledge of the structure and activation family (Derynck et al. 1987, Kaleko et al. 1990). This potent mechanism of RTKs and the signalling pathways controlled mechanism of activation occurs when a RTK is aberrantly by tyrosine kinases provided the possibility for the

162 Downloadedwww.endocrinology.org from Bioscientifica.com at 09/28/2021 02:58:10PM via free access Endocrine-Related Cancer (2001) 8 161–173 development of target-specific drugs and new anti-cancer potency and selectivity, higher in vitro and in vivo efficacy therapies (Plowman et al. 1994). Approaches towards the and decreased toxicity have emerged (Klohs et al. 1997, prevention or interception of deregulated RTK signalling Al-Obeidi & Lam 2000). include the development of selective components that target Recombinant immunotoxins provide another possibility either the extracellular ligand-binding domain or the of target-selective . They are composed of a intracellular tyrosine kinase or binding region bacterial or plant either fused or chemically conjugated (Fig. 1). to a specific ligand such as the variable domains of the heavy The most successful strategy to selectively kill tumour and light chains of mAbs or to a growth factor (Kreitman cells is the use of monoclonal (mAbs) that are 1999). Immunotoxins either contain the bacterial directed against the extracellular domain of RTKs which Pseudomonas exotoxin A or diphtheria toxin or the plant are critically involved in cancer and are expressed at the toxins ricin A or clavin. These recombinant molecules can surface of tumour cells (Fan & Mendelsohn 1998). In the selectively kill their target cells when internalized after past years, recombinant technology has made an binding to specific cell surface receptors (Frankel et al. enormous progress in the design, selection and production 2000). of new engineered antibodies and it is possible to generate The use of antisense oligonucleotides represents another humanized antibodies, human–mouse chimeric or bispecific strategy to inhibit the activation of RTKs. Antisense antibodies for targeted cancer therapy (Farah et al. 1998, oligonucleotides are short pieces of synthetic DNA or RNA Hudson 1999). Mechanistically, anti-RTK mAbs might that are designed to interact with the mRNA to block the work by blocking the ligand–receptor interaction and transcription and thus the expression of specific-target therefore inhibiting ligand-induced RTK signalling and proteins (Marcusson et al. 1999). These compounds interact increasing RTK downregulation and internalization. In with the mRNA by Watson–Crick base-pairing and are addition, by binding of mAbs to certain epitopes on the therefore highly specific for the target protein. On the other cancer cells they induce immune-mediated responses such hand bioavailability may be poor since oligonucleotides can as opsonization and complement-mediated lysis and trigger be degraded upon internalization by cellular endo- and antibody-dependent cellular cytotoxicity by macrophages or . Nevertheless, several preclinical and clinical natural killer cells. In recent years, it became evident that studies suggest that antisense therapy might be mAbs control tumour growth by altering the intracellular therapeutically useful for the treatment of solid tumours signalling pattern inside the targeted tumour cell, leading (Pawlak et al. 2000). to growth inhibition and/or apoptosis (Cragg et al. 1999). In contrast, bispecific antibodies can bridge selected surface molecules on a target cell with receptors on an effector cell triggering cytotoxic responses against the target cell Epidermal growthfactor receptor (EGFR) that is thus killed (Segal et al. 1999). Despite the toxicity family that has been seen in clinical trials of bispecific antibodies, advances in antibody engineering, characterization of The receptor (EGFR) family of tumour antigens and immunology might help to produce RTKs comprises four members: the archetypal EGFR/ErbB1, rationally designed bispecific antibodies for anti-cancer which was the first RTK to be molecularly cloned (Ullrich therapy. et al. 1984), HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4. Another promising approach to inhibit aberrant RTK The four receptors share two extracellular cysteine-rich signalling are small molecule drugs that selectively interfere domains and an intracellular portion with a long C-terminal with the intrinsic tyrosine kinase activity and thereby block tail carrying most of the autophosphorylation sites. Receptors receptor autophosphorylation and activation of downstream of the EGFR family are frequently co-expressed in various signal transducers (Levitzki 1999). The tyrphostins, which combinations and depending on the activating ligand they belong to the quinazolines, are one important group of such can form various homo- or heterodimers generating a inhibitors that compete with ATP for the ATP binding site complex signal transduction network (Alroy & Yarden 1997, at the receptor’s tyrosine kinase domain and some members Riese & Stern 1998). EGFR family members are activated have been shown to specifically inhibit the EGFR by a large group of EGF-related growth, which all contain a (Levitzki & Gazit 1995). But also potent and selective conserved EGF-like domain and are synthesized as inhibitors of receptors involved in neovascularization have transmembrane precursor proteins (Heldin 1996). These been developed and are now undergoing clinical evaluation. include EGF, transforming growth factor-α (TGFα), Using the advantages of structure-based drug design, , , heparin-binding EGF-like growth crystallographic structure information, combinatorial factor, and the large family of chemistry and high-throughput screening new structural alternatively-spliced (Burden & Yarden 1997). classes of tyrosine kinase inhibitors (TKIs) with increased These growth factors bind with different specificities and www.endocrinology.org Downloaded from Bioscientifica.com163 at 09/28/2021 02:58:10PM via free access Zwick et al.: RTKs in anti-cancer strategies affinities to EGFR, HER3 and HER4, while no ligand for autophosphorylation and constitutive signalling (Lonardo et HER2 has yet been identified. al. 1990, Brennan et al. 2000). It was shown that overexpression of HER2 led to a prolonged and enhanced cellular signalling through the MAP kinase pathway HER2 (Karunagaran et al. 1996, Harari & Yarden 2000). The RTK HER2 was originally identified as both the transforming gene in a chemically transformed rat The role ofHER2 in tumour growth cell line (Schechter et al. 1984) and as an Recently it became evident that the transforming ability of EGFR-related cDNA clone (Coussens et al. 1985), and has HER2 is linked to cell survival and the ability of HER2 to been most frequently implicated in human neoplasias and directly affect components of the machinery. cancer (King et al. 1985, Slamon et al. 1987, Hynes & Stern Progression through the cell cycle is critically dependent on 1994). active complex formation of cyclin-dependent kinases Despite the fact that no ligand is known to bind with (CDKs) with cyclin D1, which is a key regulator of G1/S high affinity to HER2, it is well known that HER2 acts as a phase transition of the cell cycle. Interestingly, cyclin D1 co-receptor for the other EGFR family members. In has been identified as a downstream target of HER2/neu in particular, either the EGFR ligands or the neuregulins that transgenic mice or HER2-overexpressing cell lines, which is bind HER3 or HER4 are able to induce heterodimer necessary for HER2/neu-induced transformation (Lee et al. formation between a high-affinity ligand binding receptor 2000). It was shown that cyclin D1 expression is upregulated and HER2. These heteromolecular interactions are of by activated HER2/neu and that blocking HER2 specifically pathophysiological relevance, because such receptor inhibits the growth of tumour cells by arresting the cells in combinations show strong mitogenic signalling and the G1 phase of the cell cycle. Concomitantly, accumulation tumorigenicity. Signalling pathways involving Ras, Src, of p27Kip1, a CDK inhibitor, and inactivation of – PI3-kinase and the MAP kinases ERK and JNK have been CDK2 complexes were seen (Lane et al. 2000). Moreover, shown to be activated by HER2-expressing cell lines and the level of c- and D-cylins, proteins that are involved seem to be important for tumour management (Zwick et al. in the sequestration of p27Kip1, decreased in the absence of 2000). functional HER2 (Neve et al. 2000). These results suggest HER2 gene mutation and high level overexpression are that HER2 induces the potentiation of cyclin E–CDK2 other potent mechanisms resulting in HER2 activation. A activity via regulation of p27Kip1 sequestration. As a single point mutation at position 664 within the consequence, HER2 overexpression deregulates the G1/S transmembrane region of HER2, encoding a change from the phase transition and results in aberrant proliferation hydrophobic valine to the negatively charged and tumour formation. Very recently it was demonstrated glutamic acid residue, renders the receptor constitutively that activation of the PI3-kinase/Akt pathway by active (Bargmann et al. 1986, Weiner et al. 1989). Although HER2-overexpressing cells promotes cell survival by the mutation is not observed in human tumours, a phosphorylating the CDK inhibitor p21Cip1 (Zhou et al. polymorphism at codon 655, which results in a valine to 2001). Phosphorylated p21Cip1 localizes to the isoleucine substitution, has been identified in the where it can form a complex with apoptosis-signal-regulating transmembrane coding region of the HER2 gene (Papewalis kinase 1 (ASK1) conferring its anti-apoptotic effect. At the et al. 1991). Performing a large-scale population-based, same time the HER2-induced cytoplasmic localization of case-control study in China, an association of the genetic p21Cip1 suppresses its growth-inhibiting activity in the HER2 polymorphism and an increased risk of , nucleus and consequently leads to HER2-mediated cell particularly among younger women, was recently identified growth. (Xie et al. 2000). Overexpression and/or gene amplification of HER2 was HER2 as a prognostic and predictive indicator found in various types of human cancer and especially in The relatively low expression level of HER2 in normal human breast where HER2 gene amplification epithelial cells is significantly enhanced in several types of has been identified with a frequency of 30% (Slamon et al. human cancers, including breast, ovarian, gastric, , 1987, 1989). Subsequently, it became evident that aberrantly bladder and carcinomas (Hynes & Stern 1994). elevated levels of HER2, either with or without gene Especially in breast cancer a significant correlation between amplification, correlated with a more aggressive progression HER2 overexpression and reduced survival of breast cancer of disease and a reduced patient survival time (Paik et al. patients exists (Slamon et al. 1987). Moreover, clinical as 1990). well as laboratory data revealed that overexpression of HER2 The mechanism underlying the oncogenic potential of an increases the metastatic potential of human breast and lung overexpressed HER2 may relate to the increased availability cancer cells and correlates with the number of lymph node for heterodimer formation and thus for high level metastases in node-positive breast cancer patients (Yu &

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Hung 2000). Therefore, HER2 expression represents a combination with paclitaxel or doxorubicin with pivotal biological marker that can help to determine more cyclophosphamide significantly increased response duration, accurately the prognosis for individual patients (Cooke et al. time to progression and survival in first-line metastatic breast 2001). cancer patients (Burris 2000, Stebbing et al. 2000). In recent years, it became evident that HER2 is also a Moreover, preclinical experiments have shown that predictive marker for responses to various therapeutic agents Herceptin modulates repair of radiation-induced DNA used in cancer therapy. It has been reported that HER2 damage and enhances radiosensitivity of HER2- overexpression negatively influences the response rate of overexpressing breast cancer cells (Pietras et al. 1999). breast tumours to chemotherapeutic agents (Yu & Hung Therefore, it seems reasonable that Herceptin should be 2000). In addition, elevated levels of a processed HER2 considered as one of the routine treatment options in extracellular domain in patients metastatic breast cancer. seem to reduce the efficacy of certain Other strategies against HER2-positive breast and combinations (Colomer et al. 2000). Of most important that are currently under development are clinical relevance is the fact that HER2 overexpression recombinant immunotoxins directed against HER2 (Dean et correlates with a lack of response to anti-oestrogen hormonal al. 1998, Maurer-Gebhard et al. 1998, Rosenblum et al. therapy (Houston et al. 1999) and confers resistance to 1999). In addition, downregulation of HER2 expression by tamoxifen, an anti-oestrogen that is administered as the usage of HER2 antisense oligonucleotides enhances the endocrine therapy in breast cancer patients. growth inhibitory and pro-apoptotic activity of several distinct chemotherapeutic agents and thus may play a role in Herceptin – the first RTK-specific anti-oncogene future cancer therapy (Roh et al. 1999). drug Several approaches towards the selective prevention and EGFR interception of HER2-relevant signalling are possible (Bange et al. 2001). When it was demonstrated that MAb 4D5, a The EGFR is frequently overexpressed in non-small cell mAb directed against the extracellular domain of HER2, lung, bladder, cervical, ovarian, kidney, and pancreatic could specifically inhibit the proliferation of HER2- cancer and occurs with very high incidence in squamous cell overexpressing tumour cell lines and prevent tumour growth carcinomas of the head and neck (Salomon et al. 1995, in nude mice, an excellent weapon towards the suppression Grandis et al. 1996, Fontanini et al. 1998). The predominant of HER2-mediated signalling was established (Hudziak et al. mechanism leading to EGFR overexpression is EGFR gene 1989, Shepard et al. 1991). Herceptin, the recombinant amplification, with more than 15 copies per cell reported in ‘humanized’ version of murine MAb 4D5 developed by certain tumours (Velu 1990). In general, elevated levels of Genentech, has passed all clinical trials and has been EGFR expression are associated with late stage of disease approved by the US Food and Drug Administration (FDA) progression and often correlate with high metastatic rate and in 1998 for treatment of women with metastatic breast cancer increased rate of tumour proliferation (Pavelic et al. 1993). (Pegram et al. 1998) (Table 1). Using Herceptin as a In addition, tumorigenic changes in EGFR activity can also single-agent therapy for HER2-overexpressing breast cancer, occur via mutations that activate the receptor in the absence responses up to 15% have been reported (Baselga et al. 1996, of ligand binding. A number of EGFR deletions have been Cobleigh et al. 1999). Application of Herceptin in identified in human cancer and most of these mutations alter

Table 1 A summary of the most successful drugs against signalling which are currently evaluated in clinical phases or have already been approved by the FDA. A more detailed description is found in the text RTK Drug Company Description Status EGFR ZD18539 Iressa AstraZeneca TKI that inhibits EGFR signalling Phase III EGFR C225 ImClone Systems MAb directed against EGFR Phase III EGFR EGF fusion protein Seragen Recombinant diphtheria toxin–hEGF fusion Phase II protein HER2 Herceptin Genentech MAb directed against HER2 Approved by the FDA in 1998 IGF-IR INX-4437 INEX USA Antisense oligonucleotides targeting IGR-IR Phase I VEGFR SU5416 SUGEN TKI that inhibits VEGFR2 Phase II VEGFR/FGFR/ SU6668 SUGEN RTK inhibition of VEGFR,FGFR and PDGFR Phase I PDGFR FDA,Food and Drug Administration; MAb,monoclonal antibody; RTK,receptor tyrosine kinase; TKI,tyrosine kinase inhibitor. www.endocrinology.org Downloaded from Bioscientifica.com165 at 09/28/2021 02:58:10PM via free access Zwick et al.: RTKs in anti-cancer strategies the extracellular ligand binding domain of the receptor and shows a significant anti-tumour effect on human breast and result in a truncated EGFR with constitutively active kinase colon cancer cells that is synergistically enhanced in function (Tang et al. 2000). combination with various cytotoxic agents (Ciardiello et al. A very potent mechanism of constitutive EGFR 2000) and is currently being evaluated in phase II clinical activation in a variety of human cancers is autocrine trials. stimulation via growth factor loops. The most prominent ligand, which is involved in autocrine growth receptor Insulin growthfactor receptor (IGFR) α activation, is TGF (Seth et al. 1999, Hsieh et al. 2000). family Coexpression of TGFα and EGFR is frequently observed in glioblastomas and squamous cell carcinomas of the head and Structurally quite different from the EGFR family are the neck where it is correlated with poor prognosis (Grandis et (IR) and the insulin-like growth factor (IGF) al. 1998). receptor (IGF-IR). Both receptors consist of two extracellular Interestingly, it was recently shown that the G α subunits, which are responsible for ligand binding, and two protein-coupled receptor (GPCR)-induced cleavage of membrane-spanning β subunits bearing the tyrosine kinase EGF-like growth factors leads to EGFR transactivation and domain and the autophosphorylation sites (Yarden & Ullrich EGFR-related signalling in cancer cells (Gschwind et al. 1988). The ligands for the two receptors include insulin, 2001). Mechanistically, GPCR stimulation activates a IGF-I and IGF-II. While insulin is mostly a metabolic metalloprotease that cleaves a transmembrane EGF-like , IGF-I and IGF-II are crucial for normal ligand precursor and allows the released growth factor to development and . Interestingly, in the transactivate the EGFR (Prenzel et al. 2001). Moreover, circulation IGFs are found to be complexed to a number of Prenzel et al. demonstrated that the metalloprotease inhibitor different IGF-binding proteins (IGFBPs), which serve as batimastat blocks bombesin-induced transactivation of the transport vehicles for these ligands and modify the stability EGFR in PC3 human cells and significantly and the proliferative effect of the growth factors (Jones & reduces the high constitutive level of EGFR tyrosine Clemmons 1995). phosphorylation (Prenzel et al. 1999). This finding suggests In the last 10 years it has been demonstrated that IGF-IR that GPCR–EGFR cross-communication plays a prominent and its ligands are involved in the pathogenesis of a variety role in the development and progression of human cancer. of human tumours, particular in breast and prostate cancer (Perks & Holly 2000, Surmacz 2000). In primary breast EGFR as a target for anti-cancer therapies tumours, IGF-I and IGF-II are predominantly expressed in Since aberrant EGFR signalling is implicated in many stromal fibroblasts surrounding the normal and malignant cancers and seems to correlate with poor prognosis, it is an breast (Gebauer et al. 1998, Rasmussen & Cullen excellent target for anti-cancer therapy (Huang & Harari 1998), whereas the IGF-IR is overexpressed in breast cancer 1999, Hong & Ullrich 2000). Currently, the monoclonal cells and shows enhanced tyrosine kinase activity (Resnik et antibody-based treatments using cetuximab (C225) represent al. 1998). These findings indicate that IGFs are able to the most successful anti-EGFR therapies (Table 1). C225 is stimulate breast growth in a paracrine manner. directed against the extracellular domain of the EGFR and Moreover, it has been demonstrated that high plasma IGF-I inhibits receptor activation and downstream signalling by levels correlate with an elevated prostate cancer risk and blocking ligand binding to the EGFR and inducing receptor several prostate cancer cell lines were shown to be internalization. The growth inhibiting and anti-tumour effect responsive to IGF-I (Chan et al. 1998). On the basis of these of C225 was shown in a variety of human cancer cells results several approaches have been initiated to develop new including pancreatic, renal and breast carcinomas (Prewett et small molecule inhibitors (Blum et al. 2000) or other al. 1998, Overholser et al. 2000). Therefore, it is now strategies to interfere with the pathogenic IGF-IR signalling undergoing a number of clinical trials either alone or in (Brodt et al. 2000) (Table 1). combination with chemotherapeutic treatments such as cisplatin, paclitaxel or gemcitabine (Baselga et al. 2000, Vascular endothelial growth factor Bruns et al. 2000, Inoue et al. 2000). receptor (VEGFR) family Inhibition of the tyrosine kinase activity by TKIs represents another promising approach towards the The vascular endothelial growth factor (VEGF) is one of the intervention of EGFR signalling in cancer cells. The most main inducers of endothelial cell proliferation and advanced of these compounds are ATP analogues of the permeability of blood vessels. The two RTKs that bind quinazoline and pyridopyrimidine family, which interact with VEGFs, VEGFR-1 and VEGFR-2, are expressed on the conserved ATP-binding site in the kinase domain of the endothelial cells during embryonic development and are the receptor and thus block EGFR activation (Levitzki 1992, key regulators for , a process which leads to the Noonberg & Benz 2000). The quinazoline ZD-1839 (Iressa) formation of new blood vessels developing from pre-existing

166 Downloadedwww.endocrinology.org from Bioscientifica.com at 09/28/2021 02:58:10PM via free access Endocrine-Related Cancer (2001) 8 161–173 ones. formation is usually quiescent in the adult only in normal development but also in tumour formation organism except for wound repair and the female menstrual and progression. Two classes of FGFRs were discovered in cycle. However, expansion of solid tumours beyond a the past. The first class comprise the four high affinity diameter of 1–2 mm requires de novo formation of a vascular FGFRs, whereas the second class is defined by low affinity network that provides the growing tumour with oxygen and FGF binding sites. Considerable evidence indicates that those essential nutrients. Many studies have provided evidence for low affinity binding sites represent heparan sulphate the role of the VEGF–VEGFR ligand–receptor system in proteoglycan molecules (HSPG) located on the cell surface. tumour vascularization and metastasis. Mechanistically, the These HSPG receptors may support the fine tuning of cell tumour secretes VEGF that in turn activates VEGFR-2 and responses to the FGFs present and also regulate their induces proliferation of stromal endothelial cells and availability and their transport within a tissue. sprouting of new blood vessels. The critical role of VEGFR-2 The first members of the large FGF family to be in the above-mentioned process was demonstrated by identified were the FGF-1 (aFGF) and FGF-2 (bFGF). They delivering of a retrovirus encoding a dominant negative were purified on the basis of their mitogenic activity towards VEGFR-2 into nude mice which prevented glioblastoma fibroblasts. Both ligands are potent for a variety xenograft growth (Millauer et al. 1994). These findings have of cells of mesodermal, ectodermal and endodermal origin opened a new avenue of cancer therapies and several (Basilico & Moscatelli 1992). In addition, they play a role as strategies have been developed for targeting the VEGFR positive regulators for endothelial and pathway (Table 1). angiogenesis (Folkman & Shing 1992). Inhibition of angiogenesis has several advantages The family of the high affinity FGFRs comprises four compared with other attempts in cancer therapy. This members: FGFR1 (flg), FGFR2 (bek), FGFR3 and FGFR4. includes the fact that endothelial cells are easily accessible Ligand binding to FGFRs induces dimerization and from the blood stream and are not likely to develop resistance phosphorylation of the cytoplasmic tyrosine residues, but full to cancer therapy, since endothelial cells are genetically activation is only achieved in the presence of heparin stable compared with tumour cells (Boehm et al. 1997). (Spivak-Kroizman et al. 1994). A common explanation is Therefore, over 20 anti-angiogenic drugs, which prevent that heparin is able to bind a number of monovalent FGFs endothelial cell proliferation directly by blocking activators allowing the formation of receptor oliogomeres, which bind of angiogenesis like the VEGF and fibroblast growth factor to the clustered FGFs. (FGF) receptors, are currently undergoing evaluation in phase I, II or III clinical trials (Table 1). For example the FGFs and FGFRs in cancer development small molecule inhibitor SU5416, which specifically inactivates VEGFR-2 (Fong et al. 1999), is the most The fact that a remarkable number of FGFs were identified advanced in clinical trials for the treatment of a variety of as isolated from tumours due to their ability to induce solid tumours (National Institutes of Health). The drug was proliferation or transformation of fibroblasts indicates their well tolerated in phase I studies and stable disease was functional role in tumorigenesis. Indeed, a number of studies demonstrated in a variety of tumours like Kaposi’s , point out that changes in the expression patterns of FGFs non-small cell , and breast may contribute to growth deregulation of human tumour cells cancer (Mendel et al. 2000, Fong et al. 1999). Another (Eguchi et al. 1992, Kornmann et al. 1997). Furthermore, it synthetic RTK inhibitor currently being evaluated is the has been demonstrated that expression of FGF-1, FGF-2 or tyrosine kinase inhibitor SU6668 that targets not only the FGF-8b in fibroblasts leads to transformation and tumour VEGFR but also the fibroblast growth factor receptor formation in nude mice. In addition, strategies to interfere (FGFR) and the -derived growth factor receptor with growth factor action, such as dominant negative FGFRs (PDGFR) (Laird et al. 2000). Both receptors are additionally or anti-sense oligonucleotides, result in impaired tumour involved in endothelial cell growth and angiogenesis. Other growth in nude mice (Becker et al. 1992, Li et al. 1994, active VEGFR-2 inhibitors that are now undergoing clinical Wang & Becker 1997, Auguste et al. 2001). These data trials are the TKIs PTK787, ZK22584 and a mAb that targets indicate that endogenous FGFs are autocrine mediators of the VEGFR-2 ligand. neoplastic cell growth. However, changes at the level of FGFRs, such as point growthfactors receptor (FGFR) mutations, elevated expression or different splicing, result in family dis-regulated FGFR signalling and have been identified in a variety of human tumours. For example, FGFR The fibroblast growth factors (FGFs) represent the largest overexpression was observed in tumours arising from family of growth factor ligands. To date more than 20 numerous tissues, including breast, prostate, , distinct members have been identified. The FGFs and their and salivary gland (Myoken et al. 1996, Shingu et designated receptors (FGFRs) appear to play critical roles not al. 1998, Giri et al. 1999). Somatic mutations in the FGFR-3, www.endocrinology.org Downloaded from Bioscientifica.com167 at 09/28/2021 02:58:10PM via free access Zwick et al.: RTKs in anti-cancer strategies similar to the activating mutations in skeletal dysplasias, (Jeffers et al. 1998). Somatic mutations in the HGFR have have been identified in and in multiple been demonstrated in childhood hepatocellular (Park et al. myeloma (Chesi et al. 1997, Capellen et al. 1999). 1999) as well as head and neck squamous cell carcinomas Since FGFR signalling shows a physiological profile of (Di Renzo et al. 2000). action that includes mitogenic and angiogenic activity and is Since HGF/SF is synthesized as a single chain precursor frequently altered in human tumours, this system might be a polypeptide devoid of biological activity and can be activated useful target for anti-cancer therapy. Suramin, a compound through a critical step involving proteolytic cleavage, this that complexes heparin-binding growth factors, such as initial step of HGF/SF activation provides a possible point FGF-2, has been shown to inhibit cell migration and of interference by potential inhibitors. In the past few years FGF-2-mediated induction of -plasminogen numerous inhibitors and antagonists have been identified activator (Takano et al. 1994). However, efficacy in clinical (Parr & Jiang 2001). These factors have demonstrated a trials is often limited by toxicity. Targeting the FGFRs was possible role in minimizing the action of HGF/SF on cancer first achieved by using a toxin chimera between FGF-2 and cells, and may be of therapeutic value in the future. the potent ribosome-inactivating protein saporin and shows anti-tumour activity towards melanoma cells expressing high RET receptor tyrosine kinase FGFR levels (Beitz et al. 1992). Another possibility to block FGFR signalling is Multiple endocrine neoplasia type 2 (MEN2) is a dominant represented by the use of small molecule inhibitors such as autosomal inherited cancer syndrome which exists in three SU6668, which interferes with FGFR tyrosine kinase different subtypes and is characterized by the development activity. SU6668 has been shown to induce striking of medullary thyroid carcinoma. The gene responsible for regression of large established human tumour xenografts and MEN2 was identified as the Rearranged during investigations are ongoing in phase I clinical trials (Laird et Transformation (RET) RTK. The RET proto-oncogene al. 2000) (Table 1). encodes a protein that is characterized by a cadherin-like and a cysteine-rich domain in the extracellular part of the Hepatocyte growthfactor receptor receptor. RET is expressed during embryogenesis in the peripheral nervous system and in the urogenital system and (HGFR) is involved in the development of the and the The receptor (HGFR), which is kidney (Edery et al. 1997). encoded by the proto-oncogene met (Naldini et al. 1991), MEN2 cancer syndromes are caused by dominant was identified as a regulator of a variety of morphogenic activating germline mutations in the RET proto-oncogene. processes like cell migration, cell scattering and invasion of For example, mutations at five different cysteine residues extracellular matrices (Birchmeier & Gherardi 1998). HGFR have been found in the extracellular domain, which result in is a disulphide-linked heterodimer with a glycosylated an unpaired cysteine and intermolecular disulphide bonding, extracellular α-chain and a β-chain, which consists of the leading to constitutively activated receptors (Chappuis- transmembrane and cytoplasmic tyrosine kinase domain Flament et al. 1998). (Giordano et al. 1989). Hepatocyte growth factor (HGF) or Interestingly, in 50% of patients with Hirschsprung scatter factor (SF), the corresponding ligand, is expressed in disease (HSCR), a disorder characterized by the absence of mesenchymal-derived cells where it is suggested to act in a enteric ganglia, gene deletions or point mutations that are paracrine manner on epithelial cells in close proximity and predicted to inactivate the RET receptor have been identified has been described as a growth modulator for hepatocytes, (Pasini et al. 1996, Eng & Mulligan 1997). Therefore, the melanocytes and in vitro (Kan et al. 1991, RET proto-oncogene is a unique example of either dominant Sonnenberg et al. 1993). Since HGF/SF is an important gain-of-function or dominant loss-of-function mutations in motility factor it might influence the migration of tumour the same gene associated with severe human disorders. cells and may facilitate invasive growth and metastasis. For example, HGF overexpression was demonstrated in a variety Platelet-derived growthfactor receptor of human tumours, such as thyroid and colorectal carcinomas (PDGFR) family and seems to have prognostic significance for non-small lung and breast cancer (Di Renzo et al. 1995, Siegfried et al. The two RTKs platelet-derived growth factor receptor 1997). HGFR mutations have been identified in patients with (PDGFR) and Kit are members of the PDGFR family. These inherited predisposition to develop multiple papillary renal proteins are characterized by an extracellular domain with cell carcinomas (HPRCC) (Schmidt et al. 1997). Most of five Ig-like domains and an intracellular tyrosine kinase these mutations lie adjacent to the kinase domain, leading to domain split by 100 amino acids. 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