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1. Introduction
2. Fibroblast growth factor
ligands and receptors
3. FGF/FGFR signal in BC
4. FGFRs role in BC treatment
5. Conclusion
6. Expert opinion
Review
Targeting fibroblast growth factorreceptor in breast cancer:a promise or a pitfall?Francesca Bedussi, Alberto Bottini, Maurizio Memo, Stephen B Fox,Sandra Sigala & Daniele Generali†
†UOM di Patologia Mammaria/US Terapia Molecolare, Azienda Istituti Ospitalieri di Cremona,
Cremona, Italy
Introduction: Fibroblast growth factors (FGFs) along with their receptors
(FGFRs) are involved in several cellular functions, from embryogenesis to
metabolism. Because of the ability of FGFR signalling to induce cell prolifera-
tion, migration and survival in cancer, these have been found to become over-
activated by several mechanisms, including gene amplification, chromosomal
translocation andmutations. New evidences indicate that FGFs and FGFRs may
act in an oncogenic fashion to promote multiple steps of cancer progression
by inducing mitogenic and survival signals, as well as promoting epithelial-
to-mesenchymal transition, invasion and tumour angiogenesis. This review
focuses on the predictive and prognostic role of FGFRs, the role of FGFR
signalling and how it may be most appropriately therapeutically targeted in
breast cancer.
Areas covered: Activation of the FGFR pathway is a common event in many
cancer types and for this reason FGFR is an important potential target in can-
cer treatment. Relevant literature was reviewed to identify current and future
role of FGFR family as a possible guide for selecting those patients who would
be poor or good responders to the available or the upcoming target therapies
for breast cancer treatment.
Expert opinion: The success of a personalised medicine approach using
targeted therapies ultimately depends on being capable of identifying the
patients who will benefit the most from any given drug. Outlining the molec-
ular mechanisms of FGFR signalling and discussing the role of this pathway in
breast cancer, we would like to endorse the incorporation of specific patient
selection biomakers with the rationale for therapeutic intervention with
FGFR-targeted therapy in breast cancer.
Keywords: breast cancer, breast cancer biological target, breast cancer therapy,
fibroblast growth factor receptor
Expert Opin. Ther. Targets (2014) 18(6):665-678
1. Introduction
In breast carcinoma (BC), the response to chemotherapy or targeted therapies variesaccording to histology and/or molecular subtypes [1-5]. Although effective regimensare currently established for invasive ductal carcinoma, the most common invasivebreast cancer, the treatment efficacy and the prognosis of other minor types ofBC are not adequately developed. Thus, the lobular histotype, the second mostcommon subtype of BCs (15%), actually shows poor responsiveness to availablechemotherapies [6,7]. BC is has been conventionally subclassified phenotypicallydepending on the expression of different receptors, such as oestrogen receptor(ER), progesterone receptor and human epidermal growth factor receptor2 (HER2) [8], but this traditional classification [1-5,9] has been augmented by
10.1517/14728222.2014.898064 © 2014 Informa UK, Ltd. ISSN 1472-8222, e-ISSN 1744-7631 665All rights reserved: reproduction in whole or in part not permitted
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expression profiling into at least five molecular subtypesnamely luminal A and luminal B (ER-positive tumours),HER2 (HER2-positive tumours), basal and normal-liketumours [10,11]. More recently, Next-Generation Sequencing(NGS) technology have identified gene alterations in fibro-blast growth factor receptor (FGFR)-1/2 that may be suitablefor selecting patients for targeted therapies, such as the combi-nation of everolimus with exemestane for treatment ofER-positive metastatic BC patients [12]. In light of this, wewould emphasise that even within the above-defined pheno-typic subtypes defined by classical markers, there is a widespectrum of tumour behaviour requiring the identificationof additional novel prognostic markers [13]. In a context ofsuboptimal medical therapies, new promising predictive bio-markers that provide potential for selecting appropriatepatients suitable for receiving new effective regimens areneeded [14,15]. Genetic variations, particularly gene amplifica-tion, chromosomal translocation and point mutation, havebeen shown to be excellent biomarkers for selection oftargeted drugs. Because a spectrum of aberrant FGFR genechanges has been associated with prostate and breasttumorigenesis [16], we focus our attention on FGFR as newtherapeutic target for treatment of BC [17-22].
2. Fibroblast growth factor ligands andreceptors
The FGFR family consists of four members, FGFR1, FGFR2,FGFR3 and FGFR4, which bind to their high-affinity ligands,
the fibroblast growth factors (FGFs) [23,24]. The FGF/FGFRsignalling pathway has been shown to mediate cell prolifera-tion, migration, motility, survival and other biologicalprocesses, including tissue repair, hematopoiesis and angiogen-esis [25]. The aberrant regulation of this pathway has beenimplicated in many forms of human malignancies [26] andaffects proliferation, anti-apoptosis, drug-resistance, epithelial-to-mesenchymal transition (EMT) and invasion [23,27-31]. Ithas also been determined that activation of the FGF/FGFRpathway leads to an increase in tumour angiogenesis and mayplay a role in tumour resistance to anti-angiogenic and otherchemotherapies [21,26].
The FGF family consists of 18 secreted glycoproteins:FGF1 (aFGF), FGF2 (bFGF), FGF3(INT2), FGF4, FGF5,FGF6, FGF7(KGF), FGF8, FGF9, FGF10, FGF16,FGF17, FGF18, FGF19, FGF20, FGF21, FGF22 andFGF23 [17]. The different FGFs and their correspondingreceptors are expressed in a tissue-specific manner, whichcontribute to the specificity of the ligand--receptor interac-tion [21,24]. FGFs are secreted glycoproteins that are generallyreadily sequestered into the extracellular matrix, as well as inthe cell surface, by heparan sulphate proteoglycans (HPSGs).To signal, FGFs are released from the extracellular matrix byheparinases, proteases or specific FGF-binding proteins, andthe liberated FGFs subsequently bind to cell surface throughthe HPSGs. HPSGs also stabilise the FGF ligand--receptorinteraction, forming a ternary complex with FGFR [32,33].The specificity of the FGF--FGFR interaction is establishedpartly not only by the differing ligand-binding capacities ofthe receptor paralogues [34,35] but also by alternative splicingof FGFR, which substantially alters ligand specificity. Othersecreted proteins facilitate the FGF--FGFR interaction [36],such as the Klotho family [37], for hormonal FGFs, whichfurther increases ligand specificity [21].
There are four FGFR genes (FGFR1, FGFR2, FGFR3 andFGFR4), located on chromosomes 8p12, 10q26, 4p16.3 and5q35.1-qter, respectively [21,38,39]. A fifth related receptor,FGFR5 (also known as FGFRL1), is capable of bindingFGFs [21]. FGFR genes are proto-oncogenes activated inhuman cancers as a result of gene amplification, chromosomaltranslocation and point mutation [17-22]. Encoded receptorsconsist of an extracellular ligand-binding domain, a single-pass transmembrane domain and an intracellular tyrosinekinase (TK) domain [24].
The extracellular domain has three Ig-like domains(IgI -- IgIII) with an acidic, serine-rich region betweendomains I and II (termed the acid box): the first Ig-likedomain, together with the acid box, plays a role in receptorauto-inhibition; the second and third Ig-like domains areresponsible for binding the FGF ligand [38,40,41]. InFGFR1 -- 3, alternative splicing in Ig-like domain III createsisoforms with different ligand-binding specificities (FGFR1IIIb, FGFR2 IIIb, FGFR3 IIIb and FGFR1 IIIc,FGFR2 IIIc, FGFR3 IIIc) [38]. The FGFR IIIb isoforms arepredominantly epithelial and the IIIc isoforms are
Article highlights.
. The fibroblast growth factors and their receptors (FGFRs)play an important role in a wide range of biologicalfunctions (cell proliferation, migration, motility, survival,tissue repair, hematopoiesis and angiogenesis).
. The aberrant regulation of this pathway has beenimplicated in many forms of human malignancies as amediator of proliferation, anti-apoptosis, drug-resistance,epithelial-to-mesenchymal transition and invasion.
. FGFR-targeted drugs exert direct as well as indirectanticancer effects through processes suchas angiogenesis.
. Based on the genetic aberrations in FGFRs identified inbreast carcinoma patients and their consequences on amolecular level, several approaches can be used totarget FGFR signalling: inhibitors of FGFR tyrosinekinases activities, therapeutic antibodies andupstream intervention.
. FGFRs amplification status could be either predictive orprognostic markers.
. FGFR pathway must be further clarified to develop drugsmore selective and targeted. Randomised Clinical Trialswill establish the subpopulation in which these drugsshould be used.
This box summarises key points contained in the article.
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predominantly mesenchymal, with their correspondingligands only activating either the epithelial or mesenchymalisoforms, except FGF1, which binds all receptor isoforms [35].Thus, paracrine signalling is achieved by, for instance,epithelial cells producing ligands that only activate the corre-sponding mesenchymal FGFR IIIc isoforms and viceversa [40].
The intracellular kinase domain is similar to the VEGFreceptor (VEGFR) and platelet-derived growth factor receptor(PDGFR) kinases in that it has an insert, resulting in a splitkinase domain [40]. FGF ligand binding to the FGFR causesreceptor dimerisation, trans-phosphorylation and activationof an intracellular TK domain that is separated into two con-tiguous active regions [21]. Several docking proteins (moleculescontaining Src homology 2 domains) bind to these phosphor-ylated residues, resulting in their phosphorylation and subse-quent activation. Major pathways downstream of activatedFGFRs include the rat sarcoma MAPK (RAS--MAPK) path-way and the phosphoinositide-3 kinase v-akt murinethymoma viral oncogene (PI3K [PIK3CA]--AKT [AKT1])pathway whose activation is mediated via FGFR substrate2a (FRS2a [FRS2]) and several other adaptor molecules,such as GRb2 [21,39,42]. FRS2 is a key adaptor protein that islargely specific to FGFRs, although it can also bind otherTK receptors, such as neurotrophic TK receptor type 1,ReT and anaplastic lymphoma kinase 12. FRS2 binds tothe juxtamembrane region of FGFRs through itsphosphotyrosine-binding domains. The activated FGFRphosphorylates FRS2 on several sites, allowing the recruit-ment of the adaptor proteins son of sevenless and growth fac-tor receptor-bound 2 (GRb2) to activate RAS and thedownstream RAF and MAPK pathways [21,24]. A separatecomplex involving GRb2-associated binding protein 1 recruitsa complex, which includes PI3K, and this activates an AKT-dependent anti-apoptotic pathway [21,43]. Downstream signal-ling can be attenuated through the induction of MAPK phos-phatases (MKPs), such as MKP3, Sprouty (Spry) proteins andSeF family members that modulate receptor signalling at sev-eral points in the signal transduction cascade [21]. Anotherprominent example is phospholipase Cg (PLCg), which bindsto a phosphotyrosine in the C-terminal tail of the activatedreceptors. PLCg hydrolyses phosphatidylinositol 4,5-bisphos-phate to produce diacylglycerol and inositol 1,4,5-triphos-phate, which trigger the release of calcium and subsequentactivation of PKC [21,40]. PKC partly reinforces the activationof the MAPK pathway by phosphorylating RAF [21]. Severalother pathways are also activated by FGFRs, depending onthe cellular context, including the p38 MAPK and JunN-terminal kinase pathways, signal transducer and activatorof transcription signalling [44] and ribosomal proteinS6 kinase 2 [45] as described in Figure 1. In this way, FGF/FGFR signals trigger a variety of responses in target cells,such as proliferation, anti-apoptosis, drug resistance, angio-genesis, EMT and invasion, that are aspects strictly implicatedin cancer biology [17].
A major deactivation pathway for RTKs, termed receptordownregulation, involves their ligand-induced internalisationby means of endocytosis, followed by degradation inlysosomes [46]. Once activated, receptors can be removedfrom the cell surface by endocytosis [47]. Internalisation ofactivated RTK by endocytosis followed by sorting to lyso-somes and subsequent degradation of the receptors is one ofthe ways cells achieve signal attenuation. After internalisation,endocytosed FGF/FGFR complexes reach early/sorting endo-somes. From here, FGFR4 is sorted mainly to the recyclingcompartment, whereas FGFR1 -- 3 are sorted mostly todegradation in the lysosomes [48].
In vertebrates, other modulators of RTK signalling includethe members of the Spry family of proteins, comprising vari-ous Spry and Spred (Spry-related proteins with enabled/vasodilator-stimulated phosphoprotein homology 1 domain)isoforms. Depending on the cell type and physiological condi-tions, Sprys and Spreds modulate RTK signalling (and some-times also modulate signalling by G-protein-coupledreceptors) by mainly repressing the MAPK pathway [49].RTK activity is tightly controlled also through the coordi-nated action of many other negative protein regulators thatfunction at multiple levels of the signalling cascade, and atdifferent time points after receptor engagement, and throughmicroRNAs that have emerged as an abundant class of small(~ 22 nucleotides) non-protein-coding RNAs that play animportant role in the negative regulation of gene expression,controlling the translational efficiency of target mRNAs [50].Suppression pathways for RTKs are important to be consid-ered because the failure of RTKs to be appropriately deacti-vated may be a cause of neoplastic growth [50,51].
3. FGF/FGFR signal in BC
3.1 Fibroblast growth factor receptor 1Several studies have identified amplifications of FGFR1 inBC [39,52]. The FGFR1 is one of the TK receptors for thepro-angiogenic FGF2, secreted by endothelial and tumourcells. Recent lines of evidence indicate that FGFR1 mayplay a significant role in the biology of BCs, in particularfor the hormonal receptor positive and/or low grade BCs [21].
A variety of FGFR abnormalities have been identified inBC. FGFR1 amplification (8p11.2 -- p12 amplicon) is foundin 8 -- 15% of all BCs [9,53,54]; it is correlated withFGFR1 protein overexpression [53,55,56] and it has been foundas well in 16 -- 27% of luminal type B BC [55]. In addition,both cytoplasmic and nuclear expression of FGFR1 are ele-vated in invasive ductal carcinoma compared to normal tissue,thus predicting worse outcomes in terms of overall survival(OS) and disease-free survival (DFS). Further, using FISHprobes on tissue microarray (TMA), FGFR1 amplificationwas shown to be more frequent in invasive BC than ductalin situ carcinoma, and these amplifications were more com-monly located in the invasive components of tumours [57].
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P
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FGF FGF
HSPG
Acidbox
Acidbox
IgI
IgIIgII
IgIIIgIII
IgIII
Grb2
Frs2
Gab1
PI3K
Grb2
Jak
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STAT
DAG + IP3
PKC
PIP2
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PDK1
AKT BAD
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Cell motility Cell survival Cell proliferation
FOXO FOS
Calcineurin
NFAT
Ca2+
PLCγ
Ras
Ras
GTP
GDP Rac
MEKKs MEKs
p53 JNK Erk1/2
Raf
Shp2
Sos
Figure 1. FGF-FGFR pathway is shown. FGF ligand binding to the FGFR causes receptor dimerisation, trans-phosphorylation
and activation of an intracellular TK domain that is separated into two contiguous active regions. Major pathways
downstream of activated FGFRs include RAS--MAPK pathway and PI3K--AKT pathway. FGF/FGFR signals trigger a variety of
responses in target cells, such as proliferation, anti-apoptosis, drug resistance, angiogenesis, EMT and invasion, that are
aspects strictly implicated in cancer biology.DAG: Diacylglycerol; EMT: Epithelial-to-mesenchymal transition; FGF: Fibroblast growth factor; FGFR: Fibroblast growth factor receptor; FRS2: FGFR substrate 2;
GRb2: Growth factor receptor-bound 2; IP3: Inositol 1,4,5-triphosphate; PI3K: Phosphoinositide-3 kinase; PLCg: Phospholipase Cg; STAT: Signal transducer andactivator of transcription; TK: Tyrosine kinase.
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As such, it is proposed the activation of FGFR1 may drive thetransition from the in situ to the invasive disease [57].
The amplification/overexpression of FGFR1 has beenrecently shown to be associated with a poor prognosis, earlyrelapse and hormone resistance [55,56]. FGFR1 amplificationremained a significant independent risk factor for poor DFSand OS in ER-positive but not in ER-negative cases [54].
The effects of FGFR1 amplification on prognosis wereconfirmed by chromogenic in situ hybridisation analysis ofTMAs and subsequent correlation of FGFR1 overexpressionto survival [54]. FGFR1 overexpression was shown to be anindependent predictor of poor OS in ER-positive tumours [54].These FGFR1-amplified ER-positive tumours are commonlyendocrine therapy-resistant -- a result of increased liganddependent and independent signalling, with enhancedMAPK activation promoting upregulation of the geneencoding cyclin D 1 [55].
The role of FGFR1 amplification in lobular carcinoma hasalso been investigated. Lobular BC usually shows poorresponsiveness to chemotherapies and often lacks targetedfor therapies. FGFR1 amplification and overexpression hasbeen detected in 43% of classic lobular carcinomas, a subtypeaccounting for 5 -- 15% of invasive BCs [9]. Recently,Brunello et al. confirmed that a subset of metastatic lobularBC harbours FGFR1 gene amplification [58], thus suggestingthat patients affected by the lobular BC positive forFGFR1 could be treated by the inhibitors of FGFR signal-ling [56,59]. Amplification of FGFR1 is uncommon inHER2-amplified tumours, thus suggesting that amplificationof FGFR1 and HER2 may be mutually exclusive ways ofactivating similar downstream pathways [54].
3.2 Fibroblast growth factor receptor 2A further link between FGFR signalling and BC has beenprovided by recent genome-wide association studies that iden-tified FGFR2 as a BC susceptibility gene [21]. Using a networkderived from 2000 transcriptional profiles, it was identifiedthat SPDEF, ERa, FOXA1, GATA3 and PTTG1 are masterregulators of FGFR2 signalling and was shown that ERaoccupancy responds to FGFR2 signalling. Their resultsindicate that ERa, FOXA1 and GATA3 contribute to theregulation of BC susceptibility genes, which is consistentwith the effects of anti-oestrogen treatment in BC preventionand suggest that FGFR2-related signalling has an importantrole in mediating BC risk [60]. A locus within an intron ofthe FGFR2 gene is consistently most strongly associatedwith BC risk [61-63].
FGFR2 amplification and enrichment was also detected inapproximately 4% of triple-negative breast tumours [21]. Intwo triple-negative FGFR2-amplified cell lines, constitutivesignalling appeared to confer a survival advantage over non-amplified cell lines [21]. The role of FGFR2 in these cancershas been confirmed by in vitro studies using a FGFR-targetedsmall molecule TK inhibitor (TKI) (PD173074) or RNAi
treatment, which reduced cell survival, blocked PI3K/AKTsignalling and induced apoptosis [21].
3.3 Fibroblast growth factor receptor 3FGFR3 gene mutations are common in certain cancers andthus this gene has been considered an oncogene. However,in some normal tissues, FGFR3 has been shown to limit cellgrowth and promote cell differentiation. Lafitte et al.’s dataraise the possibility that FGFR3 has biphasic effects duringmultistage carcinogenesis in carcinomas, acting initially as atumour suppressor through oncogene-induced senescence viasignal transducer and activator of transcriptions (STATs) acti-vation and apoptosis enhancement [64]. In this context,FGFR3 loss would help in tumour progression. Alternatively,after additional mutations have occurred in the developingtumour, decoupling FGFR3 from its canonical inhibitorypathway (STATs), FGFR3 signal might be redirected to otherintracellular factors, promoting tumour progression. In thesame way, epithelial-to-mesenchymal phenotype transitionwould reveal FGFR3 as an oncogene by coupling the receptorto MAPKs pathways. This model supports a new aspect ofFGFR3 function, explaining why in epithelial cancersFGFR3-activating mutations in epithelial cancers were associ-ated with good prognosis tumours, whereas in soft tissue can-cers, FGFR3 promoted tumour progression [64]. Nevertheless,no FGFR3 mutations have been found in BC [39,65-67].
From the clinical point of view, the presence of elevatedlevels of FGFR3 in malignant breast tissues has been demon-strated in a number of studies [68], and a significant correlationbetween elevated levels and poor survival has beenobserved [69]. The function of nuclear FGFR3 is uncertain,but proteolytically cleaved FGFR3 has been reported to trafficto the nucleus [70] and nuclear FGFR1 has recently beenreported to drive invasive behaviour of BC cells [71]. Also test-ing FGFR3 on TMAs from patients treated with tamoxifen, itwas shown that the differential expression of FGFR3 was ableto select those patients who responded from those who didnot, based on the intensity of the staining [72].
3.4 Fibroblast growth factor receptor 4A single-nucleotide polymorphism in exon 9 results in anamino acid change (substitution of a glycine residue for anarginine -- Gly388Arg) within the FGFR4 transmembranedomain and results in a positive correlation with poor prog-nostic parameters in several human cancers, including breast,colon, lung, prostate and head and neck cancers [73-79]. How-ever, its role in cancer is not yet clear [79-83]. Although all fourFGFRs signal through a similar network of pathways ingeneral, the kinase domain of FGFR1 drives stronger down-stream pathway activation than FGFR4 [84]. There is alsosome evidence that differential responses to signalling areinitiated by the FGFR1 and FGFR2 kinase domains, withmore rapid attenuation of FGFR2 signalling mediated byreceptor internalisation and degradation [21,85-87].
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Meijer et al. showed that FGFR4 may play a role in thebiological response of the tumour to tamoxifen treatment.The end points of their study were the clinical benefit of thetherapy and the progression-free survival in patients withrecurrent breast cancer. Gene mRNA levels were measuredby real-time quantitative reverse transcriptase polymerasechain reaction in 285 ER-positive frozen primary breasttumours from patients who developed recurrent disease thatwas treated with tamoxifen as first-line therapy. The studyshowed that increasing levels of FGFR4 were related with ahigher probability of tamoxifen failure [88]. Even if the com-plexity of intracellular pathways and of the cancer pathologyand physiology suggested that FGFR4 mRNA levels are notmerely associated with prognosis, FGFR4 could play a rolein the biological response of the tumour to tamoxifentreatment.
4. FGFRs role in BC treatment
FGFR-targeted drugs exert direct as well as indirect anticancereffects, as FGFRs are also expressed on endothelial cells andthereby effect angiogenesis/vasculogenesis, as well as tumori-genesis [89], based on the genetic aberrations in FGFRs identi-fied and their consequences on a molecular level in BCpatients. In this setting, several pharmaceutical companieshave developed FGFR TKIs targeting FGFR signalling [39]
that are in the early phases of clinical trials [21].
4.1 Inhibitors of FGFR TKs activitiesDual inhibition with VEGFRs has the obvious potential ben-efit of targeting two pro-angiogenic growth factors or ofsimultaneously targeting angiogenesis and tumour cell prolif-eration. However, many of these TKIs with multiple targetsare less potent against the FGFRs and it is uncertain if thiswill be a disadvantage in clinical response. Targeting multiplekinases may also increase the side effects of these compounds,limiting the ability to deliver drugs at doses required forFGFR inhibition. Consequently, several pharmaceuticalcompanies are developing highly potent and specific FGFRTKIs, which are selective over VEGFRs [21].AZD4547 (N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-
pyrazol-3-yl]-4-(3,5 diemthylpiperazin-1-yl)benzamide) is aselective inhibitor of recombinant FGFR1, 2 and 3 TKs activ-ities in vitro (IC50 values of 0.2, 2.5 and 1.8 nM, respectively)with significantly weaker activity against FGFR4 (IC50
165 nM). In vitro drug selectivity has been examined againsta diverse panel of representative human kinases andAZD4547 has been shown to inhibit recombinant VEGFR2(KDR) kinase activity with an IC50 of 24 nmol/l. However,when compared with FGFR1, this represents a selectivity ofapproximately 120-fold. Excellent selectivity for FGFR wasobserved across a range of unrelated TK and serine/threoninekinases, including IGFR (> 2900-fold), CDK2(> 50,000-fold) and p38 (> 50,000-fold). AZD4547 inhibitedrecombinant FGFR kinase activity in vitro and suppressed
FGFR signalling and growth in tumour cell lines with deregu-lated FGFR expression [25]. To date, seven trials are ongoingas displayed in Supplementary Table 1.
PD173074, a selective FGFR1 TKI, was evaluated for itsanti-angiogenic activity and anti-tumour efficacy in combina-tion with photodynamic therapy (PDT). PD173074displayed selective inhibitory activity toward FGFR1 TK at26 nM. PD173074 demonstrated (> 100-fold) selectivegrowth inhibitory action toward human umbilical vein endo-thelial cells (HUVECs) compared with a panel of tumour celllines. PD173074 (at 10 nM) inhibited the formation ofmicrocapillaries on Matrigel-coated plastic. In vivo anti-angiogenesis studies in mice revealed that oral administration(p.o.) of PD173074 (25 -- 100 mg/kg) generated dose-dependent inhibition of angiogenesis against a murinemammary 16c tumour, and significantly prolonged tumourregression was achieved with daily p.o. doses of PD173074(30 -- 60 mg/kg) following PDT compared with PDT alone(p < 0.001) [90]. Ye et al. demonstrated thatPD173074 could also inhibit the proliferation, migrationand invasion and promote the apoptosis of murine mammarytumour cell line 4T1 [91]. Sharpe et al. showed that triple-negative breast cancer cell line (CAL51) in xenografts are sen-sitive to PD173074, thus suggesting that it is active based onFGFR2 expression in this subgroup in regard to the basal-likebreast cancer [92]. However, PD173074 has been abandonedfor clinical development due to toxicity as it has a narrowtherapeutic window with relatively high toxicity, and futurestudies on the impact of pharmacological blockade ofFGFR4 will require alternative approaches [93].
Dovitinib (TKI258) is an oral multi-targeted TKI withpotent activity against receptors for VEGF, PDGF and basicFGF (bFGF). In contrast to other TKIs, it inhibits not onlyVEGFR1 -- 3 (IC50: 8 -- 13 nM) and PDGFRb (IC50:12 nM) but also FGFR1 (IC50: 8 nM), FGFR3 (IC50:9 nM) and FGFR2 (IC50: 40 nM). It, therefore, has thepotential to have anti-tumour activity through inhibition ofboth FGFR and PDGFR, as well as anti-angiogenic activitythrough inhibition of FGFR, VEGFR and PDGFR [94].
Chase et al. demonstrated that, in the Ba/F3-ZNF198-FGFR1 and BCR-FGFR1 cell lines, treatmentwith TKI258 resulted in the inhibition of cell proliferationand survival, accompanied by an inhibition of phosphoryla-tion of the respective fusion proteins, ERK and STAT5 [95].These results are similar to those demonstrated for the inhib-itors SU5402, PD173074 and PKC412 in similar Ba/F3 cellline experiments [96-98]. Chase et al. have also demonstratedactivity of TKI258 on proliferation, survival and apoptosisin both cell lines with cellular IC50 values similar to thoseobtained in the Ba/F3-ZNF198-FGFR1 cell line [95].
Andre et al. showed that dovitinib monotherapy inhibitedproliferation in FGFR1- and FGFR2-amplified, but notFGFR normal, BC cell lines and also inhibited tumourgrowth in FGFR1-amplified BC xenografts. Andre et al. alsoclinically suggested that dovitinib showed anti-tumour
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activity in FGFR-amplified BCs and may have activity in BCswith FGF pathway amplification [99].
The 4T1 and 67NR cell line models of basal-like breastcancer have been used by Issa et al. for examining the impactof FGFR inhibition on tumour growth and metastaticspread [100]. They previously showed that blocking FGFRin vitro was sufficient to inhibit Erk and PI3K signallingand to induce cell death via blockade of the latter pathway.In vivo targeting of FGFR significantly slowed tumourgrowth, but neither tumour stasis nor strong inhibition ofPI3K/Akt signalling was observed [101]. The PI3K/mamma-lian target of rapamycin (mTOR) inhibitor NVP-BEZ235robustly blocks this pathway and the combination ofdovitinib + NVP-BEZ235 had significantly better anti-tumour and anti-metastatic activities than treatment withsingle inhibitors. It is becoming clear that in vivo responseto TKIs is optimal only when tumours show high levels ofapoptosis. Indeed, the most durable tumour responses andthe highest levels of apoptosis were observed in mice treatedwith the FGFR inhibitor in combination with either thePI3K/mTOR inhibitor or the pan ErbB inhibitor [100]. Forboth treatments, a strong inhibition of the FGFR/FRS2/Erkpathway and the PI3K/Akt/mTOR pathway was observed.Thus, it has been suggested that that combinatorial inhibitionof FGFR and ErbB receptors may have a particularly signifi-cant impact on the in vivo tumour growth and metastaticspread of BC models [100]. New strategies based on dovitinibare now under development in clinical trials (SupplementaryTable 1).
Brivanib alaninate is an example of a TKI targeting bothFGFRs and VEGFRs. Its effect in BC has so far only beentested in vitro: cell lines with FGFR1 amplification/overexpression are more sensitive than non-amplifiedones [102].
Nintedanib (BIBF-1120) targets additional pro-angiogenicintracellular signalling pathways beyond VEGF signalling andhave also the potential to contribute to anticancer therapies. Ittargets not only VEGFRs but also FGFR and PDGFR [103].
NVP-BGJ398 (N-aryl-N¢-pyrimidin-4-yl ureas) has beenoptimised to afford potent and selective inhibitors of theFGFR1, FGFR2 and FGFR3 by rationally designing thesubstitution pattern of the aryl ring. Based on the in vitrodata, NVP-BGJ398 was selected for in vivo evaluation andshowed significant anti-tumour activity in RT112 bladdercancer xenograft models that overexpress wild-type FGFR3,supporting the potential therapeutic use of NVP-BGJ398 asa new anticancer agent [104].
Guagnano et al. showed that somatic mutations of FGFRfamily members predict sensitivity to NVP-BGJ398. NVP-BGJ398 inhibits FGFR1, FGFR2 and FGFR3 with singledigit nmol/l IC50 in biochemical and cellular autophosphory-lation assays and FGFR4 with 38- to 60-fold lower potency.In cellular assays, the most potently inhibited kinase, in addi-tion to the FGFRs, was found to be VEGFR2, displaying70- to 100-fold reduced potency as compared with FGFR1,
FGFR2 and FGFR3. Therefore, NVP-BGJ398 is a selective,pan-FGFR kinase inhibitor, with predominant activity onFGFR1, FGFR2 and FGFR3 [105].
Lucitanib (E-3810) is a dual inhibitor of VEGFR andFGFR TKs inhibiting the kinase activity of VEGFR1, 2 and3 and FGFR1 and 2 at nM concentrations [106]. In vitroE-3810 inhibits the VEGF- and bFGF-dependent prolifera-tion and the signalling transduction pathways elicited byVEGF and bFGF receptor binding to their receptors inHUVECs in the nM range. Much higher concentrations(µM) were needed to interfere in vitro with the growth ofdifferent cell lines in non-ligand stimulated conditions, sug-gesting that the drug effect on tumour cells occurs at quitehigh concentrations and that primary effect of the drug isinhibition of VEGF and FGF signalling pathways, whichare pivotal in the proliferation and survival of endothelialand stromal cells. In vivo 7 days of treatment withE-3810 completely inhibited the FGF-induced angiogenesisin an implanted Matrigel plug in mice; E-3810 treatmentsignificantly reduced tumour vessel density in treated tumours(as assessed by the decrease in CD31 staining) by increasingthe percentage of tumour necrosis and changing the composi-tion of tumour stroma (with a decrease in collagen IVcontent) [107]. Bello et al. also showed a striking activity ofthe E-3810--paclitaxel combination with complete, lastingtumour regressions; the anti-tumour activity of the combina-tion was also confirmed in another triple-negative breastxenograft, MX-1. The activity was superior to that of thecombinations paclitaxel + brivanib and paclitaxel + suniti-nib [108]. This drug is now in a Phase I clinical trials (Supple-mentary Table 1).
Ponatinib (AP24534) is an oral multi-targeted TKI and hasbeen explored as a pan-FGFR inhibitor in vitro and in vivousing a broad panel of engineered cell lines and cell linesderived from a variety of cancer types, including breastmodels. In all the 14 cell lines examined, ponatinib had themost potent inhibitory effect on cell growth. Ponatinibdisplayed greater potency compared with BIBF 1120 andbrivanib and dovitinib across all models, with the greatestdifferences (2- to 13-fold increased potency) observed in celllines containing dysregulated FGFR1 or FGFR2 [109].
FGFRs are expressed on various different cell types toregulate key cell behaviours and play an important role intumour cell proliferation, differentiation, survival, cell-migration and angiogenesis [91]. On this assumption, a numberof potent inhibitors of the FGFRs are in early phase clinicaltrials (Phase I or II) [110]. No drug is currently underPhase III trials. Currently there are insufficient data in breastcancer to state any one of the above therapies is better thananother. Although there some proven targeted therapies thathave radically changed the outcome of breast cancer, such asendocrine therapy for luminal-type breast cancer or trastuzu-mab for HER2-positive breast cancer, many cancer have denovo or develop resistances to targeted treatment or do nothave a target such as triple-negative breast cancer (ER,
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progesteron receptor and HER2 negative). For these patients,it is important to evaluate alternative pathway to circumventthe mechanisms of resistance. For example, exemestane withmTOR inhibitor Everolimus was used in hormone-receptor-positive, HER2-negative, advanced breast cancer, followingprogression/recurrence after endocrine therapy with aromataseinhibitors to improve patients’ outcome. The disadvantage ofthis approach is that many of the TKIs are multi-targeted drugsblocking not only the FGFRs but also PDGFR family andVEGFR family at similar concentrations and lead to increasedfrequency of treatment-related adverse events.
4.2 Therapeutic antibodiesTo minimise the side effects of targeting FGFRs, therapeuticantibodies could be used which may have substantial benefits,as they can be used in treating cancer cells that are reliant on aparticular FGFR and thereby reduce the potential toxicity ofpan-FGFR inhibition. Antibodies targeting FGFR3 havebeen shown to have an anti-proliferative effect on bladdercancer cells and myeloma. A single chain Fv antibody that tar-geted FGFR1IIIc could not be pursued further as it was foundto potentially block FGF signalling in the hypothalamus,resulting in severe anorexia in rodents and monkey models,but it still remains to be ascertained whether this would be aclass effect for all FGFR1IIIc antibodies [21].No therapeutical antibodies against FGFR or FGF are in
clinical trials in BC currently, but there are many efforts todevelop mAbs against this attractive therapeutic target. Toaddress the role of FGFR2 in tumorigenesis and to exploreFGFR2 as a potential therapeutic target, Bai et al. generateda mAb against the extracellular ligand-binding domain ofFGFR2: GP369, an FGFR2-IIIb isoform-specific mAb.GP369 inhibited the ligand-induced phosphorylation ofFGFR2 and its downstream signalling, as well as the prolifer-ation driven by FGFR2 overexpression. Administration ofGP369 in mice inhibited the in vivo growth of human cancerxenografts harbouring FGFR2 amplification [111]. Zhao et al.also generated and characterised several anti-FGFR2 mAbsand showed that they block the functional activity ofFGFR2 in vitro and inhibit growth of FGFR2 overexpressinggastric tumour xenografts in vivo. Among the three mAbsdeveloped, GAL-FR21, GAL-FR22 and GAL-FR23, the abil-ity of the GAL-FR21 and GAL-FR22 mAbs, which are highlyspecific for FGFR2, is almost to completely inhibit thegrowth of SNU-16 and OCUM-2M in xenografts providingdecisive evidence for the central role of FGFR2 in tumourgrowth [112]. These findings provide a rationale for clinicallytesting their therapeutic potential in human cancers withactivated/amplified FGFR2 signalling [113]. As all FGFRTKI drugs inhibit several TK receptors in addition toFGFR2, mAbs may compensate this loss of selectivity indecreasing adverse events.Another avenue that interferes with ligand binding is the
use of antagonistic peptide mimics, which have been designed
for FGFR1-IIIc and FGFR2-IIIb and have shown apparenttherapeutic potential [114].
4.3 Upstream interventionA further approach is to develop FGF ligand traps. FP-1039,a fusion protein, comprises the extracellular domain ofFGFR1 and the Fc region of IgG [21]. FP-1039 has beenshown to have anti-angiogenic effects in vivo. Moreover,FP-1039 was able to block tumour formation of BC cellline xenografts, depending on their expression of FGFs andFGFRs. As the FGFRs have several ligands in common, notonly FGFR1 activation but also activation of FGFR3 andFGFR4 is blocked by binding of FP-1039 to FGFs, makingFP-1039 a rather universal blocker of FGFR signalling [39,115].
To achieve blockade of the mitogenic FGFs while avoidinginhibition of hormonal FGFs, Harding et al. developed thissoluble decoy receptor. The FGFR1c isoform (FGFR1 con-taining the c-splice region in domain III) was chosen becauseit has a broad FGF ligand-binding profile and does not bindthe hormonal FGFs with high affinity in the absence ofklotho. Consistent with these findings, FP-1039 binds toand inhibits the mitogenic members of the FGF familybut exhibits little or no affinity for the hormonal FGFs.FP-1039 inhibits angiogenesis and the FGF/FGFR autocrinegrowth loops that drive tumour cell proliferation [116].
5. Conclusion
Despite improvements in BC detection and development ofnew therapeutic approaches, there are many breast cancersfor which efficacious therapies are unavailable. Kinases inhib-itors have become one of the most intensively pursued classesof drug target with many kinase targets being developed to thelevel of a Phase I clinical trial [117]. Because of the multiplemechanisms of action for FGFR inhibitors to overcomedrug resistance, FGFR-targeted therapy is a promising strat-egy for the treatment of refractory cancer [118,119]. With regardto the BC, several studies have identified amplification ofFGFRs such as FGFR1 and 2 [39,52] that play a significantrole in the biology of BCs, in particular hormonal receptor-positive and/or low-grade BCs [21]. Indeed, amplification ofFGFR’s signal is reported in up to one-third of BCs and iscorrelated with concomitant proteins’ overexpression [53,55,56].The amplification/overexpression of FGFR1 has recently beenshown to be associated with a poor prognosis, early relapseand hormone resistance [55,56], supporting the rationale fortargeting the FGF/FGFR family members. The use of thesechanges as biomarkers for patient selection is seen in the studyof Shiang et al. which demonstrated growth inhibition by bri-vanib, an FGFR1 inhibitor correlated with FGFR1 DNAcopy number, mRNA and its protein expression measuredin 21 cell lines [102]. Among non-amplified cells, there wasno correlation between FGFR1 mRNA or protein expressionlevels and brivanib sensitivity. Two of three FGFR1 amplifiedcells were sensitive to bFGF-induced growth stimulation,
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which was blocked by brivanib. In cells with amplifiedFGFR1, brivanib decreased receptor autophosphorylation,inhibited bFGF-induced TK activity and reduced phosphory-lation of ERK and AKT. These finding suggest that FGFRfamily amplification or protein overexpression in breastcancers may be an indicator of anti-FGFR inhibitor-basedtreatment. The most advanced approaches for targeting theFGFR network are small molecule-like inhibitors of FGFRTK activities and blocking antibodies for specific receptorsor ligands. Nevertheless, two important points that need tobe considered when considering these drugs are, in particular,the FGFR inhibitor activity and the potential side effects ofblocking FGFRs. First, the selection of patients by physiciansis through molecular testing to determine tumour-specificgene amplification and/or protein overexpression as indicatorsfor sensitivity. Second, as many of TKIs are multi-targeteddrugs because they block at similar concentrations not onlythe FGFRs but also PDGFR family and VEGFR family, theside-effects profile need to be managed. In conclusion,although there are still some clinical problems to be over-come, there is good evidence suggesting that targeting FGFRsin certain subtypes of BC would be a valuable approach inthe future.
6. Expert opinion
The FGFs and FGFRs play an important role in a wide rangeof biological functions, controlling developmental events suchas brain patterning, morphogenesis and limb developmentwith multiple physiological functions in the adult, includingangiogenesis, wound repair and endocrine functions. Themajority of FGFs bind receptor in a trimeric complex withheparins, triggering a conformational change in the receptorthat leads to activation of the FGFR that results in phosphor-ylation of multiple sites on the intracellular domain, adapterprotein binding and intracellular signalling. The deregulationof FGF signalling in cancer results in activation of the path-way without appropriate regulation leading to/contributingto development of cancer, promoting cancer cell proliferation,survival and migration. Activation of the FGFR pathway is acommon event in many cancer types, and for this reasonFGFR is an interesting potential target in cancer treatment.Up to now several therapeutic approaches have been in usein clinical trials. Multiple different therapeutics are underdevelopment, so it is important to consider whether differenttherapeutic approaches lend themselves to specific oncogenicaberrations. Possible way to target FGFR pathway are mAbsbinding FGFR, ligand traps or downstream blockage, butthey are still in a very premature development phase. How-ever, the most advanced in clinical development are TKIs.Different FGFR TKIs vary substantially in potency againstFGFRs. Kinases with constitutive ligand-independent activa-tion, through mutation or amplification, are generally moresensitive to TKIs than wild-type receptors. The first genera-tion of inhibitors, represented by multi-targeting ATP
competitive inhibitors or the second generation of inhibitorswhich selectively target FGFRs with an undoubted higherpotency are the most tested in clinical trials. The mostadvanced first-generation small molecules inhibiting FGFRare TKI258 (dovitinib) or/and BMS540215 (brivanib).Dovitinib targets FGFR, PDGFR and VEGFR. In aPhase II trial, treatment with dovitinib induced stable diseasefor > 6 months in the 25% of patients with FGFR1-amplifiedER-positive and HER2-negative metastatic breast cancer [120].Also recent data showed that the overexpression of FGFR1 inassociation with the mutational status of the PI3K could helpin understanding those patients who will have the benefitfrom the combination therapies such as the exemestaneand everolimus.
The multiple different mechanisms through which FGFsignalling can be activated necessitate a complex approach toclinical development. Only a subset of breast cancers is likelyto be sensitive to FGFR inhibitors, and screening will berequired to specifically identify cancers with amplification.One approach is to screen a very large number of patients;another approach is to potentially combine different cancertypes with the same genetic aberration into a single trial butthis requires the target and its downstream effect to be thesame in different cancer subtypes. This has shown not to bethe case with BRAF inhibition in melanoma and colorectalcancer, for example, the current knowledge suggests thatFGFRs amplification status could be not only a predictiveand prognostic marker, but it could be also a potential anti-tumour target and that FGFRs inhibition could be a validapproach for a selected subpopulation of breast cancer patient,probably in association with conventional therapies.
Importantly, concrete progresses are being made in under-standing how FGF signalling may impact breast cancerpathogenesis and progression, but we are only at the begin-ning of understanding how, and in which cancers, FGFsignalling might be targeted for therapeutic benefit. Severalquestions arise about combination of FGFR inhibitors andstandard chemotherapy or how FGFR signalling affects theresponse to chemotherapy. While we are waiting for furtherscientific and clinical research to clarify the potential role ofFGFR targeting in breast cancer treatment, we believe theproper questions, in order to be ready when the drug will beavailable for the oncologist, are related to ‘how could we selectthe proper patient for the appropriate anti-FGFR drug?’.
The real success will depend on understanding additionalpharmacokinetic and pharmacodynamic factors that influenceanti-tumour efficacy of these drugs targeting FGFRs, whichare in development. Another practical issue that faces the clin-ical development of these targeted therapies is the validation,in tandem, of predictive markers for treatment sensitivityand resistance. Moreover the assay for such biomarkers shouldhave sufficient sensitivity to detect low-frequency aberrations,in routine paraffin-embedded specimen, particularly astumour cells can be heterogeneous and background materialof normal tissue cannot be avoided. Ideally, this should be
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incorporated into a platform that is capable of multiplextesting of a large panel of candidate genes to fully utilise thetypically small quantity of tumour genetic material available,such as a mass-array system or NGS, with some assays allow-ing copy number to be determined. However, this requiresdedicated technological, human and financial resources thatmay not be readily available for the community practitioner,thereby requiring sending to a reference laboratory. Althoughimmunohistochemical and TMA methods are readily avail-able in pathology laboratories, this might be a feasibleapproach, although this may be hampered by availability ofrelevant antibodies, optimisation required and the generalpoor concordance in community laboratories with referencelaboratories in quantitative testing. There is also a need tounderstand both intrinsic and acquired resistance to serialbiopsies along each patient’s treatment course that will enable
elucidation of the genetic or signalling events that mediateacquired treatment resistance will be required. More impor-tantly, when multiple agents having similar spectrum of activ-ity are being developed contemporaneously by different drugcompanies, there should be a collaborative effort in develop-ing new study designs that will permit an efficient means ofclinical testing, in a fashion akin to what has been spearheadedby the I-SPY2 investigators. This is a highly pertinent concernparticularly when the patient population for clinical trials islimited by the low prevalence rate of an oncogenic drugtarget.
Declaration of interest
The authors state no conflict of interest and have received nopayment in preparation of this manuscript.
BibliographyPapers of special note have been highlighted as
either of interest (�) or of considerable interest(��) to readers.
1. Berruti A, Generali D, Kaufmann M,
et al. International expert consens us on
primary systemic therapy in the
management of early breast cancer:
highlights of the fourth symposium on
primary systemic therapy in the
management of operable breast cancer,
cremona, italy (2010). J Natl Cancer
Inst Monogr 2011;2011(43):147-51
2. Tung N. What is the optimal endocrine
therapy for postmenopausal women with
hormone receptor-positive early breast
cancer? J Clin Oncol
2013;31(11):1391-7
3. Cardoso F, Loibl S, Pagani O, et al. The
european society of breast cancer
specialists recommendations for the
management of young women with
breast cancer. Eur J Cancer
2012;48(18):3355-77
4. Arslan UY, Turker I, Aksoy S, et al.
Duration of anti-HER2 blockage therapy
may improve survival in HER2 positive
metastatic breast carcinoma patients.
J BUON 2013;18(3):585-93
5. Chen X, Ye G, Zhang C, et al. Superior
outcome after neoadjuvant chemotherapy
with docetaxel, anthracycline, and
cyclophosphamide versus docetaxel plus
cyclophosphamide: results from the
NATT trial in triple negative or
HER2 positive breast cancer.
Breast Cancer Res Treat
2013. [Epub ahead of print]
6. Brunello E, Brunelli M, Manfrin E, et al.
Classical lobular breast carcinoma
consistently lacks topoisomerase-IIalpha
gene amplification: implications for the
tailored use of anthracycline-based
chemotherapies. Histopathology
2012;60:482-8
7. Vergine M, Brunelli M, Martignoni G,
et al. Suitability of infiltrative lobular
breast carcinoma for anti-human
epidermal growth factor receptor
2 treatment after the ASCO/CAP and
2009 St gallen international expert
consensus meeting. Histopathology
2010;57:935-40
8. Reis-Filho JS, Pusztai L. Gene expression
profiling in breast cancer: classification,
prognostication, and prediction. Lancet
2011;378(9805):1812-23
9. Weigelt B, Horlings HM, Kreike B,
et al. Refinement of breast cancer
classification by molecular
characterization of histological special
types. J Pathol 2008;216(2):141-50
10. Sørlie T, Tibshirani R, Parker J, et al.
Repeated observation of breast tumor
subtypes in independent gene expression
data sets. Proc Natl Acad Sci USA
2003;100:8418-23
11. Perou CM, Sørlie T, Eisen MB, et al.
Molecular portraits of human breast
tumours. Nature 2000;406:747-52
12. Hortobagy GN, Martine J,
Piccart-Gebhart MJ, et al. Correlation of
molecular alterations with efficacy of
everolimus in hormone receptor--positive,
HER2-negative advanced breast cancer:
results from BOLERO-2. 2013 ASCO
annual meeting. J Clin Oncol
2013;31(Suppl):abstract LBA509
13. Madden SF, Clarke C, Aherne ST, et al.
BreastMark: an integrated approach to
mining publicly available transcriptomic
datasets relating to breast cancer
outcome. Breast Cancer Res
2013;15(4):R52
14. Gozgit JM, Wong MJ, Moran L, et al.
Ponatinib (AP24534), a multitargeted
pan-FGFR inhibitor with activity in
multiple FGFRamplified or mutated
cancer models. Mol Cancer Ther
2012;11:690-9
15. Patel RR, Sengupta S, Kim HR, et al.
Experimental treatment of oestrogen
receptor (ER) positive breast cancer with
tamoxifen and brivanib alaninate, a
VEGFR-2/FGFR-1 kinase inhibitor:
a potential clinical application of
angiogenesis inhibitors. Eur J Cancer
2010;46:1537-53
16. Schwertfeger KL. Fibroblast growth
factors in development and cancer:
insights from the mammary and prostate
glands. Curr Drug Targets
2009;10(7):632-44
17. Katoh M, Nakagama H. FGF receptors:
cancer biology and therapeutics.
Med Res Rev 2014;34(2):280-300
18. Grose R, Dickson C. Fibroblast growth
factor signalling in tumorigenesis.
Cytokine Growth Factor Rev
2005;16:179-86
19. Katoh M. Cancer genomics and genetics
of FGFR2. Int J Oncol 2008;33:233-7
20. Ivan M, Matei D. Blockade of FGF
signalling: therapeutic promise for
F. Bedussi et al.
674 Expert Opin. Ther. Targets (2014) 18(6)
Exp
ert O
pin.
The
r. T
arge
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y R
MIT
Uni
vers
ity o
n 06
/03/
14Fo
r pe
rson
al u
se o
nly.
ovarian cancer. Cancer Biol Ther
2010;10:505-8
21. Turner N, Grose R. Fibroblast growth
factor signalling: from development to
cancer. Nat Rev Cancer
2010;10(2):116-29
. The paper is a very well-explained
review of the molecular mechanisms of
FGFR pathway and it helps the readers
to understand how FGF signalling can
be an appropriate target for
cancer treatment.
22. Greulich H, Pollock PM.
Targetingmutant fibroblast growth factor
receptors in cancer. Trends Mol Med
2011;17:283-92
23. Heinzle C, Sutterluty H, Grusch M,
et al. Targeting fibroblast-growth-factor-
receptor-dependent signalling for cancer
therapy. Expert Opin Ther Targets
2011;15:829-46
24. Eswarakumar VP, Lax I, Schlessinger J.
Cellular signalling by fibroblast growth
factor receptors. Cytokine Growth
Factor Rev 2005;16(2):139-49
25. Gavine PR, Mooney L, Kilgour E, et al.
AZD4547: an orally bioavailable, potent,
and selective inhibitor of the fibroblast
growth factor receptor tyrosine kinase
family. Cancer Res 2012;72(8):2045-56
26. Kono SA, Marshall ME, Ware KE, et al.
The fibroblast growth factor receptor
signalling pathway as a mediator of
intrinsic resistance to EGFR-specific
tyrosine kinase inhibitors in non-small
cell lung cancer. Drug Resist Updat
2009;12(4-5):95-102
27. Katoh Y, Katoh M. FGFR2-related
pathogenesis and FGFR2-targeted
therapeutics. Int J Mol Med
2009;23:307-11
28. Ota S, Zhou ZQ, Link JM, et al. The
role of senescence and prosurvival
signalling in controlling the oncogenic
activity of FGFR2 mutants associated
with cancer and birth defects.
Hum Mol Genet 2009;18:2609-21
29. Korc M, Friesel RE. The role of
fibroblast growth factors in tumor
growth. Curr Cancer Drug Targets
2009;9:639-51
30. Nilsson EM, Brokken LJ, Harkonen PL.
Fibroblast growth factor 8 increases
breast cancer cell growth by promoting
cell cycle progression and by protecting
against cell death. Exp Cell Res
2010;316:800-12
31. Cuevas P, Carceller F, Angulo J, et al.
Antiglioma effects of a new, low
molecular mass, inhibitor of fibroblast
growth factor. Neurosci Lett
2011;491:1-7
32. Harmer NJ, Ilag LL, Mulloy B, et al.
Towards a resolution of the
stoichiometry of the fibroblast growth
factor (FGF)-FGF receptor-heparin
complex. J Mol Biol 2004;339(4):821-34
33. Mohammadi M, Olsen SK,
Ibrahimi OA. Structural basis for
fibroblast growth factor receptor
activation. Cytokine Growth Factor Rev
2005;16(2):107-37
34. Zhang X, Ibrahimi OA, Olsen SK, et al.
Receptor specificity of the fibroblast
growth factor family. The complete
mammalian FGF family. J Biol Chem
2006;281(23):15694-700
35. Ornitz DM, Xu J, Colvin JS, et al.
Receptor specificity of the fibroblast
growth factor family. J Biol Chem
1996;271(25):15292-7
36. Wu DQ, Kan MK, Sato GH, et al.
Characterization and molecular cloning
of a putative binding protein for heparin-
binding growth factors. J Biol Chem
1991;266:16778-85
37. Kurosu H, Ogawa Y, Miyoshi M, et al.
Regulation of fibroblast growth factor-23
signaling by klotho. J Biol Chem
2006;281(10):6120-3
38. Beenken A, Mohammadi M. The FGF
family: biology, pathophysiology and
therapy. Nat Rev Drug Discov
2009;8:235-53
39. Tenhagen M, van Diest PJ, Ivanova IA,
et al. Fibroblast growth factor receptors
in breast cancer: expression, downstream
effects, and possible drug targets.
Endocr Relat Cancer
2012;19(4):R115-29
40. Wesche J, Haglund K, Haugsten EM.
Fibroblast growth factors and their
receptors in cancer. Biochem J
2011;437(2):199-213
41. Olsen SK, Ibrahimi OA, Raucci A, et al.
Insights into the molecular basis for
fibroblast growth factor receptor
autoinhibition and ligand-binding
promiscuity. Proc Natl Acad Sci USA
2004;101(4):935-40
42. Acevedo VD, Ittmann M, Spencer DM.
2009 paths of FGFR-driven
tumorigenesis. Cell Cycle
2009;8(4):580-8
43. Altomare DA, Testa JR. Perturbations of
the AKT signaling pathway in human
cancer. Oncogene 2005;24(50):7455-64
44. Hart KC, Robertson SC, Kanemitsu MY,
et al. Transformation and Stat activation
by derivatives of FGFR1, FGFR3, and
FGFR4. Oncogene 2000;19:3309-20
45. Kang S, Elf S, Dong S, et al. Fibroblast
growth factor receptor 3 associates with
and tyrosine phosphorylates p90 RSK2,
leading to RSK2 activation that mediates
hematopoietic transformation.
Mol Cell Biol 2009;29:2105-17
46. Peschard P, Park M. Escape from
Cbl-mediated downregulation:
a recurrent theme for oncogenic
deregulation of receptor tyrosine kinases.
Cancer Cell 2003;3(6):519-23
47. Casaletto JB, McClatchey AI. Spatial
regulation of receptor tyrosine kinases in
development and cancer. Nat Rev Cancer
2012;12:387-400
48. Haugsten EM, Malecki J, Bjørklund SM,
et al. Ubiquitination of fibroblast growth
factor receptor 1 is required for its
intracellular sorting but not for its
endocytosis. Mol Biol Cell
2008;19(8):3390-403
49. Cabrita MA, Christofori G. Sprouty
proteins, masterminds of receptor
tyrosine kinase signaling. Angiogenesis
2008;11:53-62
50. Ledda F, Paratcha G. Negative regulation
of receptor tyrosine kinase (RTK)
signaling: a developing field.
Biomark Insights 2007;2:45-58
51. Dikic I, Giordano S. Negative receptor
signalling. Curr Opin Cell Biol
2003;15(2):128-35
52. Moelans CB, de Weger RA,
Monsuur HN, et al. Molecular profiling
of invasive breast cancer by multiplex
ligation-dependent probe amplification-
based copy number analysis of tumor
suppressor and oncogenes. Mod Pathol
2010;23(7):1029-39
53. Andre F, Job B, Dessen P, et al.
Molecular characterization of breast
cancer with high-resolution
oligonucleotide comparative genomic
hybridization array. Clin Cancer Res
2009;15(2):441-51
54. Elbauomy Elsheikh S, Green AR,
Lambros MB, et al.
FGFR1 amplification in breast
carcinomas: a chromogenic in situ
Targeting fibroblast growth factor receptor in breast cancer
Expert Opin. Ther. Targets (2014) 18(6) 675
Exp
ert O
pin.
The
r. T
arge
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y R
MIT
Uni
vers
ity o
n 06
/03/
14Fo
r pe
rson
al u
se o
nly.
hybridisation analysis. Breast Cancer Res
2007;9(2):R23
55. Turner N, Pearson A, Sharpe R, et al.
FGFR1 amplification drives endocrine
therapy resistance and is a therapeutic
target in breast cancer. Cancer Res
2010;70(5):2085-94
56. Massabeau C, Sigal-Zafrani B, Belin L,
et al. The fibroblast growth factor
receptor 1 (FGFR1), a marker of
response to chemoradiotherapy in breast
cancer? Breast Cancer Res Treat
2012;134(1):259-66
57. Jang MH, Kim EJ, Choi Y, et al.
FGFR1 is amplified during the
progression of in situ to invasive breast
carcinoma. Breast Cancer Res
2012;14(4):R115
58. Brunello E, Brunelli M, Bogina G, et al.
FGFR-1 amplification in metastatic
lymph-nodal and haematogenous lobular
breast carcinoma. J Exp Clin Cancer Res
2012;31:103
59. Brunello E, Brunelli M, Bogina G, et al.
FGFR-1 amplification in metastatic
lymph-nodal and haematogenous lobular
breast carcinoma. J Exp Clin Cancer Res
2012;31:103
60. Fletcher MN, Castro MA, Wang X,
et al. Master regulators of
FGFR2 signalling and breast cancer risk.
Nat Commun 2013;4:2464
61. Michailidou K, Hall P,
Gonzalez-Neira A, et al. Large-scale
genotyping identifies 41 novel breast
cancer susceptibility loci. Nat Genet
2013;45(4):392-8; 398e1-2
62. Couch FJ, Wang X, McGuffog L, et al.
Genome-wide association study identifies
novel breast cancer susceptibility loci.
Nature 2007;447(7148):1087-93
63. Hunter DJ, Kraft P, Jacobs KB, et al.
A genome-wide association study
identifies alleles in FGFR2 associated
with risk of sporadic postmenopausal
breast cancer. Nat Genet
2007;39(7):870-4
64. Lafitte M, Moranvillier I, Garcia S, et al.
FGFR3 has tumor suppressor properties
in cells with epithelial phenotype.
Mol Cancer 2013;12:83
65. Sibley K, Stern P, Knowles MA.
Frequency of fibroblast growth factor
receptor 3 mutations in sporadic
tumours. Oncogene
2001;20(32):4416-18
66. Koziczak M, Holbro T, Hynes NE.
Blocking of FGFR signalling inhibits
breast cancer cell proliferation through
downregulation of D-type cyclins.
Oncogene 2004;23(20):3501-8
67. Greenman C, Stephens P, Smith R, et al.
Patterns of somatic mutation in human
cancer genomes. Nature
2007;446(7132):153-8
68. Glenisson M, Vacher S, Callens C, et al.
Identification of new candidate
therapeutic target genes in triple-negative
breast cancer. Genes Cancer
2012;3(1):63-70
69. Kuroso K, Imai Y, Kobayashi M, et al.
Immunohistochemical detection of
fibroblast growth factor receptor 3 in
human breast cancer: correlation with
clinicopathological/molecular parameters
and prognosis. Pathobiology
2010;77(5):231-40
. In clinical routine,
immunohistochemistry is a rapid,
useful and cheap approach for
detection of targets important for the
oncological treatment decision making.
The paper showed data about the
methodology to identify member of
FGFR family and information about
their clinical impact as
prognostic markers.
70. Degnin CR, Laederich MB, Horton WA.
Ligand activation leads to regulated
intramembrane proteolysis of fibroblast
growth factor receptor 3. Mol Biol Cell
2011;22(20):3861-73
71. Chioni AM, Grose R. FGFR1 cleavage
and nuclear translocation regulates breast
cancer cell behavior. J Cell Biol
2012;197(6):801-17
72. Tomlinson DC, Knowles MA, Speirs V.
Mechanisms of FGFR3 actions in
endocrine resistant breast cancer.
Int J Cancer 2012;130(12):2857-66
73. Streit S, Bange J, Fichtner A, et al.
Involvement of the FGFR4 Arg388 allele
in head and neck squamous cell
carcinoma. Int J Cancer
2004;111(2):213-17
74. Morimoto Y, Ozaki T, Ouchida M,
et al. Single nucleotide polymorphism in
fibroblast growth factor receptor 4 at
codon 388 is associated with prognosis in
high-grade soft tissue sarcoma. Cancer
2003;98(10):2245-50
75. Spinola M, Leoni V, Pignatiello C, et al.
Functional FGFR4 Gly388Arg
polymorphism predicts prognosis in lung
adenocarcinoma patients. Cancer
2003;98(10):2245-50
76. da Costa Andrade V, Parise O, Hors C,
et al. The fibroblast growth factor
receptor 4 (FGFR4) Arg388 allele
correlates with survival in head and neck
squamous cell carcinoma.
Exp Mol Pathol 2007;82(1):53-7
77. Frullanti E, Berking C, Harbeck N, et al.
Meta and pooled analyses of
FGFR4 Gly388Arg polymorphism as a
cancer prognostic factor. Eur J
Cancer Prev 2011;20(4):340-7
78. Marme´ F, Hielscher T, Hug S, et al.
Fibroblast growth factor receptor 4 gene
(FGFR4) 388Arg allele predicts
prolonged survival and platinum
sensitivity in advanced ovarian cancer.
Int J Cancer 2012;131(4):E586-91
79. Dutra RL, de Carvalho MB,
Dos Santos M, et al. FGFR4 profile as a
prognostic marker in squamous cell
carcinoma of the mouth and oropharynx.
PLoS One 2012;7(11):e50747
80. Becker N, Nieters A, Chang-Claude J.
The fibroblast growth factor receptor
gene Arg388 allele is not associated with
early lymph node metastasis of breast
cancer. Cancer Epidemiol
Biomarkers Prev 2003;12(6):582-3
81. Jezequel P, Campion L, Joalland MP,
et al. G388R mutation of the
FGFR4 gene is not relevant to breast
cancer prognosis. Br J Cancer
2004;90(1):189-93
82. Spinola M, Leoni VP, Tanuma J, et al.
FGFR4 Gly388Arg polymorphism and
prognosis of breast and colorectal cancer.
Oncol Rep 2005;14(2):415-19
83. Streit S, Mestel DS, Schmidt M, et al.
FGFR4 Arg388 allele correlates with
tumour thickness and FGFR4 protein
expression with survival of melanoma
patients. Br J Cancer
2006;94(12):1879-86
84. Vainikka S, Joukov V, Wennstr€om S,
et al. Signal transduction by fibroblast
growth factor receptor-4 (FGFR-4).
Comparison with FGFR-1. J Biol Chem
1994;269(28):18320-6
85. Freeman KW, Gangula RD, Welm BE,
et al. Conditional activation of fibroblast
growth factor receptor (FGFR) 1, but
not FGFR2, in prostate cancer cells leads
to increased osteopontin induction,
extracellular signal-regulated kinase
F. Bedussi et al.
676 Expert Opin. Ther. Targets (2014) 18(6)
Exp
ert O
pin.
The
r. T
arge
ts D
ownl
oade
d fr
om in
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ahea
lthca
re.c
om b
y R
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vers
ity o
n 06
/03/
14Fo
r pe
rson
al u
se o
nly.
activation, and in vivo proliferation.
Cancer Res 2003;63(19):6237-43
86. Xian W, Schwertfeger KL, Rosen JM.
Distinct roles of fibroblast growth factor
receptor 1 and 2 in regulating cell
survival and epithelialmesenchymal
transition. Mol Endocrinol
2007;21(4):987-1000
87. Freeman KW, Welm BE, Gangula RD,
et al. Inducible prostate intraepithelial
neoplasia with reversible hyperplasia in
conditional FGFR1-expressing mice.
Cancer Res 2003;63(23):8256-63
88. Meijer D, Sieuwerts AM, Look MP,
et al. Fibroblast growth factor receptor
4 predicts failure on tamoxifen therapy
in patients with recurrent breast cancer.
Endocr Relat Cancer 2008;15(1):101-11
89. Daniele G, Corral J, Molife LR,
de Bono JS. FGF receptor inhibitors:
role in cancer therapy. Curr Oncol Rep
2012;14:111-19
. As FGFR pathway is relevant as
therapeutic target, the review gives a
clear overview of the current clinical
status of agents targeting FGFRs.
90. Dimitroff CJ, Klohs W, Sharma A, et al.
Anti-angiogenic activity of selected
receptor tyrosine kinase inhibitors,
PD166285 and PD173074: implications
for combination treatment with
photodynamic therapy.
Invest New Drugs 1999;17(2):121-35
91. Ye T, Wei X, Yin T, et al. Inhibition of
FGFR signaling by PD173074 improves
antitumor immunity and impairs breast
cancer metastasis. Breast Cancer
Res Treat 2014;143(3):435-46
.. The role of the immune system in
cancer and cancer treatment is
increasing. The paper shows how
FGFR inhibition not only targets the
tumour but also modulates the
immune response providing a new
insight in the therapeutic approach for
breast cancer.
92. Sharpe R, Pearson A,
Herrera-Abreu MT, et al. FGFR
signaling promotes the growth of triple-
negative and basal-like breast cancer cell
lines both in vitro and in vivo.
Clin Cancer Res 2011;17(16):5275-86
93. Crose LE, Etheridge KT, Chen C, et al.
FGFR4 blockade exerts distinct
antitumorigenic effects in human
embryonal versus alveolar
rhabdomyosarcoma. Clin Cancer Res
2012;18(14):3780-90
94. Wang X, Kay A, Anak O, et al.
Population pharmacokinetic/
pharmacodynamic modeling to assist
dosing schedule selection for dovitinib.
J Clin Pharmacol 2013;53(1):14-20
95. Chase A, Grand FH, Cross NC. Activity
of TKI258 against primary cells and cell
lines with FGFR1 fusion genes associated
with the 8p11 myeloproliferative
syndrome. Blood 2007;110(10):3729-34
96. Demiroglu A, Steer EJ, Heath C, et al.
The t(8;22) in chronic myeloid leukemia
fuses BCR to FGFR1: transforming
activity and specific inhibition of
FGFR1 fusion proteins. Blood
2001;98(13):3778-83
97. de Brito LR, Batey MA, Zhao Y, et al.
Comparative pre-clinical evaluation of
receptor tyrosine kinase inhibitors for the
treatment of multiple myeloma.
Leuk Res 2011;35(9):1233-40
98. Chen J, Deangelo DJ, Kutok JL, et al.
PKC412 inhibits the zinc finger 198-
fibroblast growth factor receptor 1 fusion
tyrosine kinase and is active in treatment
of stem cell myeloproliferative disorder.
Proc Natl Acad Sci USA
2004;101(40):14479-84
99. Andre F, Bachelot T, Campone M, et al.
Targeting FGFR with dovitinib
(TKI258): preclinical and clinical data in
breast cancer. Clin Cancer Res
2013;19(13):3693-702
100. Issa A, Gill JW, Heideman MR, et al.
Combinatorial targeting of FGF and
ErbB receptors blocks growth and
metastatic spread of breast cancer models.
Breast Cancer Res 2013;15(1):R8
101. Dey JH, Bianchi F, Voshol J, et al.
Targeting fibroblast growth factor
receptors blocks PI3K/AKT signalling,
induces apoptosis, and impairs mammary
tumor outgrowth and metastasis.
Cancer Res 2010;15:4151-62
102. Shiang CY, Qi Y, Wang B, et al.
Amplification of fibroblast growth factor
receptor-1 in breast cancer and the effects
of brivanib alaninate. Breast Cancer
Res Treat 2010;123(3):747-55
103. Rolfo C, Raez LE, Bronte G, et al. BIBF
1120/nintedanib: a new triple
angiokinase inhibitor-directed therapy in
patients with non-small cell lung cancer.
Expert Opin Investig Drugs
2013;22(8):1081-8
104. Guagnano V, Furet P, Spanka C, et al.
Discovery of 3-(2,6-dichloro-3,5-
dimethoxy-phenyl)-1-{6-[4-(4-ethyl-
piperazin-1-yl)-phenylamino]-pyrimidin-
4-yl}-1-methyl-urea (NVP-BGJ398), a
potent and selective inhibitor of the
fibroblast growth factor receptor family
of receptor tyrosine kinase. J Med Chem
2011;54(20):7066-83
105. Guagnano V, Kauffmann A, W€ohrle S,
et al. FGFR genetic alterations predict
for sensitivity to NVP-BGJ398, a
selective pan-FGFR inhibitor.
Cancer Discov 2012;2(12):1118-33
. In the era of personalised medicine,
the paper showed data about the
molecular profiles, useful in clinic, of
potential predictors with sensitivity to
FGFR inhibitors.
106. Chen TW, Bedard PL. Personalized
medicine for metastatic breast cancer.
Curr Opin Oncol 2013;25(6):615-24
107. Bello E, Colella G, Scarlato V, et al.
E-3810 is a potent dual inhibitor of
VEGFR and FGFR that exerts antitumor
activity in multiple preclinical models.
Cancer Res 2011;71(4):1396-405
108. Bello E, Taraboletti G, Colella G, et al.
The tyrosine kinase inhibitor E-3810
combined with paclitaxel inhibits the
growth of advanced-stage triple-negative
breast cancer xenografts.
Mol Cancer Ther 2013;12(2):131-40
109. Gozgit JM, Wong MJ, Moran L, et al.
Ponatinib (AP24534), a multitargeted
pan-FGFR inhibitor with activity in
multiple FGFR-amplified or mutated
cancer models. Mol Cancer Ther
2012;11(3):690-9
110. Cortes JE, Kim DW, Pinilla-Ibarz J,
et al. A phase 2 trial of ponatinib in
Philadelphia chromosome-positive
leukemias. N Engl J Med
2013;369(19):1783-96
111. Bai A, Meetze K, Vo NY, et al. GP369,
an FGFR2-IIIb-specific antibody,
exhibits potent antitumor activity against
human cancers driven by activated
FGFR2 signaling. Cancer Res
2010;70(19):7630-9
112. Zhao WM, Wang L, Park H, et al.
Monoclonal antibodies to fibroblast
growth factor receptor 2 effectively
inhibit growth of gastric tumor
xenografts. Clin Cancer Res
2010;16(23):5750-8
113. Ceccarelli S, Romano F, Angeloni A,
et al. Potential dual role of KGF/KGFR
as a target option in novel therapeutic
strategies for the treatment of cancers
Targeting fibroblast growth factor receptor in breast cancer
Expert Opin. Ther. Targets (2014) 18(6) 677
Exp
ert O
pin.
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r. T
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om in
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ahea
lthca
re.c
om b
y R
MIT
Uni
vers
ity o
n 06
/03/
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r pe
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nly.
and mucosal damages. Expert Opin
Ther Targets 2012;16(4):377-93
114. Li S, Christensen C, Kiselyov VV, et al.
Fibroblast growth factor-derived peptides:
functional agonists of the fibroblast
growth factor receptor. J Neurochem
2008;104(3):667-82
115. Zhang H, Masuoka LB, Sadra AB, et al.
2007 LT FP-1039 (FGFR1:Fc),
A soluble FGFR1 receptor antagonist,
inhibits tumor growth and angiogenesis.
AACR-NCI-ERTC International
Conference, San Francisco 2007. p. B55
116. Harding TC, Long L, Palencia S, et al.
Blockade of nonhormonal fibroblast
growth factors by FP-1039 inhibits
growth of multiple types of cancer.
Sci Transl Med 2013;5(178):178ra39
117. Zhang J, Yang PL, Gray NS. Targeting
cancer with small molecule kinase
inhibitors. Nat Rev Cancer
2009;9(1):28-39
118. Liang G, Liu Z, Wu J, et al. Anticancer
molecules targeting fibroblast growth
factor receptors. Trends Pharmacol Sci
2012;33(10):531-41
119. Hynes NE, Dey JH. Potential for
targeting the fibroblast growth factor
receptors in breast cancer. Cancer Res
2010;70(13):5199-202
.. The paper is a clear overview of FGFR
signal transduction inhibitors focused
on breast cancer.
120. Andre F, Bachelot T, Campone M, et al.
Targeting FGFR with dovitinib
(TKI258): preclinical and clinical data in
breast cancer. Clin Cancer Res
2013;19:3693-702
.. The translational approach is
fundamental in understanding the new
drugs, which are available, as it helps
the clinicians to treat their patients.
The paper is a very interesting
translational study moving from the
bench to the bedside on a FGFR
inhibitor in breast cancer.
AffiliationFrancesca Bedussi1, Alberto Bottini2,
Maurizio Memo1, Stephen B Fox3,
Sandra Sigala1 & Daniele Generali†2
†Author for correspondence1University of Brescia Medical School,
Department of Molecular and Translational
Medicine, Section of Pharmacology, Brescia, Italy2UOM di Patologia Mammaria/US Terapia
Molecolare, Azienda Istituti Ospitalieri di
Cremona, Viale Concordia 1, 26100,
Cremona, Italy
E-mail: [email protected] MacCallum Cancer Centre, St Andrews
Place, East Melbourne, Victoria, 3002, Australia
Supplementary material available online
Supplementary Table 1.
F. Bedussi et al.
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