Lung Cancer 63 (2009) 169179

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Lung Cancer

journa l homepage: www.e lsev ier .com

Review

MET as

Nicole A. Rava Section of Hem cago, Ib Department o edicalc Scripps Memo

a r t i c l

Article history:Received 21 MAccepted 15 Ju

Keywords:METHGFAnti-MET-therChest tumorsLung cancerMesothelioma

beennd it, and, angnd mtion,getedsedrur proructuptor i

1. Introduction

Thoracic tumors, including those of the lung and bronchus, areestimated tin the yearmalignant myear1, witthree decador overexping lung anepithelial o(HGF), andsignaling caonic develoepithelial-mFurthermoreration andmorphogen

The funmutation ochanges incesis, altered

Corresponland Avenue, Mfax: +1 773 83

E-mail add

cellular changes induced by MET dysregulation deems it a power-ful therapeutic target, andnewdrugs targeted againstMET andHGFare currently being investigated in vitro and in vivo,with promising

0169-5002/$ doi:10.1016/j.lo account for 213,380 new cases and 160,390 deaths2007 in the US [1]. Furthermore, the incidence ofesothelioma in the US is between 2000 and 3000 per

h an estimated 250,000 deaths in Europe in the nextes [2,3]. The receptor tyrosine kinase MET is mutatedressed in a large variety of human cancers, includ-d mesothelioma. MET is expressed mainly on cells ofrigin, is activated by its ligand hepatocyte growth factoris responsible for triggering a number of intracellularscades [47]. MET and HGF are required for embry-pment, as Met and HGF-null mice display defects inesenchymal transition during organogenesis [810].e, MET and HGF play important roles in cell prolif-survival, angiogenesis, cell migration and invasion,

ic differentiation, and tissue organization [11,12].ction of MET in human tumors can be enhanced byr amplication of this receptor, leading to oncogenicluding cell proliferation, reduced apoptosis, angiogen-cytoskeletal function and metastasis. This myriad of

ding author at: Section of Hematology/Oncology 5841 South Mary-C 2115, Chicago, IL 60637, United States. Tel.: +1 773 702 4399;

4 1798.ress: rsalgia@medicine.bsd.uchicago.edu (R. Salgia).

results. In this review, we will describe the basic biology of MET aswell as its potential for therapeutic targeting. (See Refs. [1316] forother MET reviews)

2. MET structure and function

The gene for MET is located on chromosome 7q21-q31, andit is 120kb in length with 21 exons and 20 introns. The proteinconsists of a 50kD extracellular alpha chain and a 140kD trans-membrane beta chain, which are linked by disulde bonds. It bearssimilarity to the family of Ron and Sea kinases [17,18]. It con-tains the following domains: sema, PSI (in Plexins, Semaphorins,Integrins), four IPT repeats (in Immunoglobulins, Plexins, Tran-scription factors), TM (transmembrane), JM (juxtamembrane) andTK (tyrosine kinase) [see Fig. 1a]. The JM domain contains 2 pro-tein phosphorylation sites: S985 and Y1003. Phosphorylation ofS985 negatively regulates kinase activity [19] and phosphoryla-tion of Y1003 recruits c-Cbl, which monoubiquinates MET andinteracts with endophilin, targeting MET for internalization anddegradation [2022]. The TK domain contains numerous tyrosinephosphorylation sites: Y1230, Y1234 and Y1235 are involved inautophosphorylation and initiation of tyrosine kinase activity [23];Y1313 assists in activation of P13K and recruitment of p85 [24];Y1349 and Y1356 are multi-substrate docking sites for SH2 (Srchomology-2), PTB (phosphotyrosine binding) andMDB (MET bind-

see front matter 2008 Elsevier Ireland Ltd. All rights reserved.ungcan.2008.06.011a target for treatment of chest tumors

Cipriania,b, Oyewale O. Abidoyec, Everett Vokesa,atology/Oncology, Department of Medicine, University of Chicago Medical Center, Chi

f Pathology, and University of Chicago Cancer Research Center, University of Chicago Mrial Hospital, La Jolla, CA 92037, United States

e i n f o

ay 2008ne 2008

apeutics

a b s t r a c t

The receptor tyrosine kinase MET hasand mesothelioma. The MET receptor ain cell growth, survival and migrationchanges including tumor proliferationnon-small cell lung cancer (NSCLC), avia overexpression, constitutive activaepigeneticmechanisms. Newdrugs tarand invivo,withpromising results. TheincludingMET expression at the RNA ofunction. This paper will review the sttherapeutic inhibition of the MET rece/ locate / lungcan

i Salgiaa,b,

L 60637, United StatesCenter, Chicago, IL 60637, United States

studied of a large variety of human cancers, including lungs ligand HGF (hepatocyte growth factor) play important rolesdysregulation of the HGF-MET pathway leads to oncogeniciogenesis and metastasis. In small cell lung cancer (SCLC),alignant pleural mesothelioma (MPM), MET is dysregulatedgene amplication, ligand-dependent activation, mutation oragainstMET andHGF are currently being investigated in vitrogs functionat a varietyof stepswithin theHGF-METpathway,

tein level, the ligand-receptor interaction, and tyrosine kinasere, function, mechanisms of tumorigenesis, and potential forn lung cancer and mesothelioma.

2008 Elsevier Ireland Ltd. All rights reserved.

170 N.A. Cipriani et al. / Lung Cancer 63 (2009) 169179

Fig. 1. MET st ins);(transmembra ); NSCMPM (maligna

ing domainmorphogen

METs liscatter factocells [28]. Iization, autcatalytic ac

Tyrosinetively regulsubstrates svate signal tERK2, and Fits C-termintor protein[23,26,323The PI3K pathe Erk pathate cell adhand invasioing morphpathways [and Gab1-Ctal proteinsmotility andkinase anddependencebindingparfrom other

3. MET in t

Becauseof mechaniBoth MET aplastic tissu

expron oncergerMET

etastion ot, thsion,ructure; SEMA (semaphorin-like); PSI (found in plexins, semaphorins, and integrne); JM (juxta-membrane); TK (intracellular tyrosine kinase); S (serine); Y (tyrosinent pleural mesothelioma).

)-containing proteins [25,26]; Y1365 is involved in cellesis [27].gand is HGF (hepatocyte growth factor) also known asr, which is secreted by broblasts and smooth musclet binds METs sema domain and induces MET dimer-ophosphorylation, and activation of tyrosine kinasetivity [2931].phosphorylation of JM, TK, and tail domains respec-ate internalization, catalytic activity, and docking of

of overMutatiious camurinetion ofand malterat

Firsexpresuch asGab-1, Grb2, Shc, c-Cbl, which subsequently acti-ransducers such as PI3Kinase, PLC-gamma, STAT, ERK1,AK [see Fig. 2]. METs uniqueness as an RTK stems fromal multi-substrate docking site and its unique adap-

Gab-1, whichmediates numerousMET-initiated signals5]. Gab-1 activates both the Erk and PI3K pathways.thway mediates cell survival via the Akt/PKB pathway;way mediates mitogenesis; and both pathways medi-esion, motility, and invasion [3640]. Cell migrationn are mediated by Ras, Crk, and c-src/FAK, and branch-ogenesis further requires the STAT3 and PLCgamma4151]. Specically, activation of Ras-Rac1/Cdc42-PAKrk-C3G-Rap1 regulates cell adhesion and cytoskele-. Molecules involved in the regulation of MET-inducedmigration include cadherins, integrins, focal adhesionpaxillin [52]. Furthermore, the temporal and spatialof MET-signaling and its interactions with non-kinase

tners (suchas focal adhesioncomplexes)deemituniqueRTKs [5355].

umorigenesis

of their diverse biological functions, there are a varietysms by which MET and HGF inuence tumorigenesis.nd HGF have been shown to be overexpressed in neo-e relative to normal surrounding tissue, and the extent

paracrine/anetic mechoncogenes)cancer tissuNSCLC casesubcategoriof large cellof SCLCs stactivity witcell, 71% ofdemonstratsite; 33% ofdemonstratsite [59]. Ipatients shexpressionmutation w13% of smalmalignant pover-expres

Second,lation and istromal celligand-indeoverexpresstruncation,activation aIPT (found in ig-like regions, plexins and transcription factors); TMLC (non-small cell lung carcinoma); SCLC (small cell lung carcinoma);

ession correlates with disease severity and outcome.r amplication of the MET gene has been shown in var-types, and introduction of Met or HGF transgenes intom cells induces neoplastic growth. Contrarily, inhibi-or HGF reverses cell proliferation, motility, invasion,

asis in vivo. Tumorigenesis is affected by mutation orf the MET pathway in numerous ways.e regulation of MET may be altered via over-constitutive kinase activation, gene amplication,utocrine activation via HGF, MET mutation or epige-anisms (tumor secreted growth factors, hypoxia, other[5658] [see Fig. 3]. In protein studies of human lunges, Ma et al. demonstrated MET expression in 100% ofs studied, of which 61% stained strongly [59]. Whenzed, 67% of adenocarcinomas, 60% of carcinoids, 57%carcinomas, 57% of squamous cell carcinomas and 25%rongly expressed MET. When assessing for functionalh p-MET staining, 44% of adenocarcinomas, 86% of largesquamous cell, 40% of carcinoids and 100% of SCLCsed MET phosphorylation at the Y1003 c-Cbl bindingadenocarcinomas, 57% of large cell and 50% of SCLCsed MET autophosphorylation at the Y1230/1234/1235n other studies of lung adenocarcinoma, 4172% ofowed MET expression and 2567% showed MET over-in comparison to adjacent normal tissue [6063]. METas detected in 8% of lung adenocarcinoma patients andl cell lung carcinoma patients [64]. In studies of humanleural mesothelioma tissues, 82% demonstrated METsion [65].the regulation of HGF may be altered via HGF upregu-ncreased circulating HGF originating from tumor andls [12]. Third, the MET pathway may be activated in apendent manner, including activating MET mutations,ion and constitutive ligand-independent dimerization,translocation, rearrangement, hypoxic activation, trans-nd loss of inhibitory regulators [6673]. Fourth, MET

N.A. Cipriani et al. / Lung Cancer 63 (2009) 169179 171

Fig. 2. The MET pathway; PYK2 (protein tyrosine kinase 2); PXN (paxillin); FAK (focal adhesion kinase); SOS (son of sevenless); GRB2 (growth factor receptor-bound protein2); GABI (GRB2-associated binding protein 1); RHO (ras homolog gene family); RAC1 (Ras-related C3 botullinum toxin substrate 1); CDC42 (cell division cycle 42); PI3K(phosphoinositide 3 kinase); JAK (janus kinase); STAT (signal transducers and activators of transcription).

gene mutation or amplication may promote tumorigenesis, suchas the germlinemissensemutation inhereditarypapillary renal cellcarcinoma, TK domain mutations, JM domain mutations, and semadomain mutations [64,7479]. These may be present in both pri-mary tumors and nodal, lung, and liver metastases [8082]. Fifth,MET activation and constitutive phosphorylation also affects neo-plastic growth, as MET is highly expressed in renal cell carcinomas,

lung adenocarcinomas and colorectal carcinomas, and it is highlyphosphorylated in lung adenocarcinoma, other adenocarcinomas,and head and heck cancer [13]. Finally, MET may act as a prognos-tic maker: in NSCLC, MET and HGF levels correlate with prognosticparameters and poor survival [60,83]. Patients withmetastatic dis-ease demonstrate higher MET expression at metastatic sites andhigher plasma MET levels [8491].Fig. 3. MET regulation.

172 N.A. Cipriani et al. / Lung Cancer 63 (2009) 169179

There have been over 20 mutations identied in MET, most fre-quently they are missense mutations located in the TK domain,although mutations in a number of other domains have been iden-tied [77,92binding to Hton, cellmoactivity. Muactivate ME

Recentlyexposure hworms expT1010I deming abnormin these wotion and abexposed tosuch as higincreased gphology [94insult sufcfunctions aof dysfuncticancer in huthrough smthe risk of d

4. MET in S

Prior reNSCLC [14,1were publisand 32 pairwere identistage SCLC,tions affect[75]. Theythan TPR-MBaF3cells. Tratio of neuprojection lT1010I cellswild type Mmigration,constitutivepaxillin Y31tion and R9unique semed: E168Dprogressionbeen a prevsema 3B analternativelextracellulaidentied ainsertion cavariable exprelation bet

In phospto HGF-indphorylationproteins invcell cycle Gsis (AKT1 a1/2, ERK 1

response (MAPKK 3/6, p38-MAPK and JNK) and cytoskeletal func-tions (FAK, adducin- and adducin-). On the other hand, HGFinhibited phosphorylation of PKC, PKC/, PKC, PKR and CKD1

ctivadowhelpgene

T in N

T muncerndin9]. Tin 1d S10ons wn1 tisuesn 14not otudiecatioT exptissuof Nntiaasivein noin adT amlly aal. dC827f theped ging

8 gecatioma ppli

d no2].Hntialplic

hasionoundumbtissuxilliocar1 pa, moinomma (ivatio

celationorylwnste vile ination] [see Fig. 1b]. Mutations in the sema domain affectGF, those in the JM domain affect the actin cytoskele-

tility andmigration. They are also regulators of catalytictations in the TK domain facilitate oligomerization andT in the absence of HGF [93]., the combined effects of MET mutation and nicotineave been demonstrated in C. elegans [94]. Transgenicressing the gain of function mutations R988C andonstrated decreased viability and vulval defects includ-al vulval hyperplasia. Additional abnormal phenotypesrms included growth arrest, uncoordinated locomo-

normal body morphology and size. Furthermore, thosenicotine demonstrated increased abnormal phenotypesher incidence of vulval defects, decreased viability,rowth arrest, locomotion defects and altered bodymor-]. In thismodel, themutations serve as an initial geneticient to cause abnormalities, and exposure to nicotines a second hit that increases the incidence and severityon. ThisC. elegansmodelparallels tumorigenesis of lungmans, with genetic mutation and exposure to nicotineoking serving as two hits that could potentially increaseeveloping cancer.

CLC

search has shown MET overexpression in SCLC and5,95]. The rst activating mutations of MET in SCLChed byMa et al. in 2003. They studied 10 SCLC cell linesed tissues. Two unique JM domain missense mutationsed: R988C was found in 2 cells lines with extensiveand T1010I was found in 1 cell line. These JM muta-MET signaling and the metastatic potential of cells

cause IL-3 independent proliferation, although lowerET (whichhas constitutively activatedMET) transfectedhe JM domain mutations also cause increased relativerite-like projections per cell and increased neurite-likeength as relative neurite-length index. Both R988C andshowed less cell-spreading and less cell-adhesion thanET cells. They also showed increased average speed offocus formation, anchorage-independent growth, andtyrosine phosphorylation of cell proteins (including). T1010I cells showed increased motility and migra-88C cells had a higher percentage of migration. Onea domain missense somatic mutation was also identi-was found in 1 cell line and may have a role in tumorvia aberrant semaphorin signaling. Of note, there hasiously reported homozygous deletion of 3p21.3 whered 3F are located [9698]. Ma et al. also identied any spliced transcript that was missing exon 10 in ther domain, present in 1 cell line. In 2 cell lines, they2bp insertion in intron 13 in the pre-JM domain. Thisn cause skipping of the entire JMdomain [75]. Althoughression of MET was present in the tumor lines, no cor-ween expression and mutation was revealed [75].hoproteomics studies of SCLC cell lines, in additionuced MET phosphorylation, HGF also induced phos-of a number of downstream proteins. These includeolved in transcriptional control (STAT3 and CREB), the1-S checkpoint (RB and RB1), cell survival and apopto-nd JNK), cell proliferation and differentiation (MAKPP, ERK 2 and ERK 1/2), stress and the inammatory

[99]. Aety ofeffectstumori

5. ME

MElung catheir sues [5foundsue, anmutatifound iin 3 tising exoMET iset al. sampli

MENSCLCin 61%preferethe invfoundfound

MEespeciaman etthe HCtions odevelocontainfrom 1amplicarcinoMET amwho hation [10to pote

Ampaxillinexpreswere fcopy nysis ofbothpaof adenmore, 2studiednocarccarcino

Actsimilarstimulphosphand doS6K. Thmolecuphoryltion of MET in SCLC subsequently activates a vari-nstream signaling pathways, and these wide-ranging

account for the important role that MET plays insis.

SCLC

tations have also been documented in non-small cell. Two years after the SCLCmutations, Ma et al. reportedgs from 4 NSCLC cell lines and 127 adenocarcinoma tis-hree JM domain mutations were identied: R988C wascell line, both R988C and T1010I were found in 1 tis-58Pwas found in 1 tissue. Four sema domainmissenseere identied: E168Dwas found in 1 tissue, L229Fwasssue, S323Gwas found in1 tissue, andN375Swas found. They also identied an alternative splice variant miss-in the JM domain, which was present in 1 tissue [59].nly mutated but is also amplied in NSCLC. Lutterbachd 9 NSCLC cell lines, of which 22% demonstrated METn, up to 2.5-fold greater than normal levels [100].ression has been shown to be present in 100% of thees and 89% of the cell lines. Therewas strong expressionSCLC, 60% of carcinoid, and 25% of SCLC. Interestingly,l expression of activated p-MET was demonstrated in

front of NSCLC tumor tissues. No MET staining wasrmal lung tissue. Increased MET mRNA expression wasenocarcinoma, carcinoid, and SCLC [59].plication has also been documented in lung cancer,fter treatment with tyrosine kinase inhibitors. Engel-emonstrated the development of MET amplication inNSCLC cell line after exposure to increasing concentra-tyrosine kinase inhibitor getinib [101]. Cells lines thatetinib resistance contained amplication of the MET-region 7q31.17q33.3. In an assessment of tumor tissuetinib-resistant NSCLC patients, 22% demonstrated METn [101]. Bean et al. also studied tissue from lung adeno-atients with getinib or erlotinib resistance, and foundcation in 21%. On the other hand, only 3% of patientst been treatedwith these drugs showedMET amplica-ence, amplicationof theMEToncogene allows tumorsly overcome therapeutic inhibition of growth signals.ation of focal adhesion signaling molecules such ass also been demonstrated in lung cancer. Increasedand increased copy numbers of both paxillin and METin 38% of NSCLC cell lines tested; however, increaseders of paxillin alone were found in 25% [103]. In anal-e from 66 NSCLC patients, increased copy numbers ofn andMETwere found in17%of large cell carcinomas, 8%cinomas and 13% of squamous cell carcinomas. Further-xillinmutationswere found among 9.4% of lung cancersre frequently in large cell carcinoma (18.4%) than ade-a (8.6%), squamous cell carcinoma (6%), or small cell0%) [103].n of the HGF-MET signaling pathway in NSCLC induceslular events as those seen in SCLC. HGF-inducedof adenocarcinoma induced autophosphorylation,

ation of the c-Cbl binding epitope in the JM domain,ream phosphorylation of PI3K, PDK-1, AKT, mTOR, andability of MET-expressing cells was decreased by smallhibitor SU11274. It also inhibited HGF-induced phos-of MET and downstream signaling [59].

N.A. Cipriani et al. / Lung Cancer 63 (2009) 169179 173

6. MET in mesothelioma

Most recently, a similar role for MET in malignant pleu-ral mesothJagadeeswamesothelioand 66 tissT1010I wastissue.Ofnoited the momolecule inidentied: Nalso found ain 1 tissue [

Positivemesothelioin 33% of ththe 1 nonmtimes highe

In threetion and inanother thamolecule Sdecreased mautophosphdownstreameffects of siexpression,migration [

7. Therape

Asdemoesis of numnon-small cFurthermorshown to abcell growthtarget. Therserve as potcurrently inpathway [se

7.1. MET ex

Small inthe MET prand effectiveffects of silung cancer1-treated cand expressing (includi-FGF, andnon-small cby inhibitinautophosphtope, AKT psmall cell las well as d[99]. siRNAaswell ashucancer. All ctumor cell

AKTandp44/42mitogen-activatedprotein kinase), decreasedHGF-dependent scattering and invasion, and increased apoptosis [105].

Short hairpin RNA (shRNA) acts in a similar fashion to siRNA,hai

utterncerstratcreaERKnitialnt acatio[100]e effro RNg RNllulaocestidescleavtheiwaseletewass imin), mIntet-7),ir-21GFRAngc ant; antan bsuppnizesy. Olgonile c[107

xpresd inew cmpozymavinan gstomeduccell csingePC3-stateexpren [11decd induceentlyf a Mtionnonellsd Mgrowelioma has been demonstrated. In a recent paper,ran et al. reported their nding from 6 malignantma cell lines, 1 nonmalignant mesothelioma cell line,ues [65]. Two JM domain mutations were identied:present in 2 cell lines, and G1085X was present in 1te, the2MPMcell lineswith theT1010Imutationexhib-st dramatic reduction of cell growth with the smallhibitor SU11274. Three sema domain mutations were375S, M431V and N454I, each present in 1 tissue. Theyn alternative splicing isoform missing exon 10, present65].MET expression was found in 82% of malignant pleuralmamicroarray specimens. Robust expressionwas founde MPM cell lines and minimal expression was found inalignant cell line. Serum HGF and EGF levels were twor in MPM patients than controls [65].MPM cell lines, HGF induced MET receptor internaliza-creased growth. The growth of these three lines (plust was not sensitive to HGF) was inhibited by the smallU11274. It also inhibited wound closure and causedigrational velocity of H28 cells in vitro. It inhibited

orylation ofMET, phosphorylation of the c-Cbl site, andphosphorylation of ERK1/2 and AKT. Similar to the

RNA in NSCLC, siRNA inMPM also down-regulatedMETwith resulting inhibition of cell growth, viability and65].

utics

nstrated,METplays an important role in the tumorigen-erous thoracic tumors, including small cell lung cancer,ell lung cancer, and malignant pleural mesothelioma.e, various inhibitors of theHGF/METpathwayhavebeenrogate tumor growth. Because of its prominent role inand motility, MET represents a powerful therapeutice are a variety of steps in the MET pathway that mayential targets, and there already exist a number of drugsdevelopment in vitro and in vivo that antagonize thise Fig. 4].

pression at the RNA level

terference RNA (siRNA) acts to suppress expression ofotein by binding to ribosomes in place of MET RNAely silencing MET RNA. Cassinelli et al. investigated theRNA and the tyrosine kinase inhibitor RPI-1 in humancell lines H460 and N592. Both the siRNA and RPI-

ells demonstrated down-regulation of MET activationion, inhibition of HGF-dependent downstream signal-ng AKT and Paxillin), decreased expression of VEGF anddecreased growth, motility and invasiveness [104]. Inell lung cancer, siRNA effectively silenced theMET genegMETprotein expression. It also inhibitedHGF-inducedorylation, phosphorylation of the c-Cbl binding epi-hosphorylation, and cell growth and viability [59]. Inung cancer, siRNA down-regulated the MET receptorownstream p-MET, p-AKT, p-ERK1/2 and p-S6 kinasehas also been shown effective in mouse breast cancermanprostate cancer, sarcoma, glioblastomaandgastricancers displayed decreasedMET expression, decreasedgrowth and viability, decreased signaling (including

but itscells. Llung cademonand depAKT,pwere iadhereamplidowncould b

MicforminIntraceand prnucleo(1) bysilencecancerwere dcancermiRNAcadhertargetswith leand mgets VEtargetsSpecimir-23RNAs ctumorantagotherapto antamolecumiRNAlet-7 eresultetively nbe an i

Riboand clein humGlioblaMET, rtumorpossescell linsteadyVEGFinvasiostratedreduceties, re

Recform otranslahumanThese cMET antumorrpin structure must be cleaved after induction intobach et al. investigated the effects of shRNA on humancell lines EBC-1 and H1993. The shRNA-treated cells

ed growth inhibition, G1S cell cycle arrest, apoptosissed tyrosine phosphorylation of -catenin, -catenin,andRas. Furthermore, theseMET-ampliedcells,whichly rounded and non-adherent, became attened andfter treatment with shRNA. Cell lines without METn were not responsive to shRNA-mediatedMET knock-. METs role in cell growth, proliferation and motilityectively silenced by RNA interference.A (miRNA) is another form of single-stranded hairpin-A that is thought to regulate gene expression.

rly, it is cleaved into partially double-stranded RNAsed into mature miRNA strands of approximately 22. These miRNAs regulate gene expression in two ways:ing mRNA and (2) by pairing with target mRNAs tor translation [106,107]. The role of miRNA in humanrst discovered in CLL, in which two miRNA genesd [108]. Reduced expression of let-7 miRNA in lunginitially reported by Takamizawa in 2004 [109]. Otherplicated in lung cancer include mir-9 (which targets E-ir-32 (which targets Integrin V), mir-124a-3 (which

grin 1), mir-30a-5p (which targets Integrin 3 alongmir-26a-1-prec (which targets Integrin 5), mir-145

8-2 (which target Paxillin), mir181-c-prec (which tar-1), mir-155 (which targets HIF-1), mir-124a1 (whichiopoietin 1), andmir-30a-5p (which targets PAI-1) [110].i-METmiRNAs includemir-1/206,mir-199a,mir-34 andi-HGF miRNAs include mir-26 and mir-190 [110]. Microe overexpressed (as oncogenes) or underexpressed (asressors) in human cancers, and treatment that eitheror restores miRNA function can serve as anti-cancer

igonucleotides called antagomirs have been designedze oncogenic miRNA; conversely, viral vectors or smallompounds could serve to enhance tumor suppressor]. For example, in lung cancer cell lines with reducedsion, overexpression of let-7 via expression constructsa 79% reduction in the number of colonies [109]. A rela-oncept in tumor biology, miRNA has already proven tortant therapeutic target.es also silence MET protein expression by binding tog RNA based on sequence. They have proven effectivelioblastoma, prostate cancer, and colorectal carcinoma.a cells demonstrated reduced expression of HGF anded HGF-dependent signal transduction, and decreasedlonogenicity, tumorigenicity and tumor growth in cellsan autocrine HGF-MET loop [111]. The prostate cancer-LN4, grown inmousemodels, demonstrateddecreasedMET levels, decreased Src kinase activity, decreasedssion, and decreased tumor growth, migration and2]. The colorectal carcinoma cell line KM20 demon-

reased cMET autophosphorylation and kinase activity,vitro growth rates and soft-agar colony-forming abili-d in vivo growth, and decreased metastasis [113]., Stabile et al. demonstrated that anti-sense DNA in theET antisense/U6 expression plasmid was able to blockof mRNA into protein. This technique was effective in-small cell lung tumors in vitro and in mice xenografts.showed decreased HGF-dependent phosphorylation ofAP kinase, down-regulation of MET protein, decreasedth, and increased rates of apoptosis [114].

174 N.A. Cipriani et al. / Lung Cancer 63 (2009) 169179

Fig. 4. Anti-M(heat shock pr

7.2. MET ex

Geldanamfunction byactivated intyrosine kinmaturationgrowth andtosis [15].geldanamycHGF-depenof this cell l

Ligandrlocalized tomediated inof the METligand, or p

The HGFdomain) iscontainingteins are weof HGF foror autocrinlar MET-actlines with Ninvasion inination in mET therapeutics; RNA (ribonucleic acid); siRNA (small interference RNA); shRNA (short hotein); HGF (hepatocyte growth factor); Ab (antibody); RTK (receptor tyrosine kinase); P

pression at the protein level

ycin or members of the anisomycin antibiotic familyinhibiting the heat shock protein HSP90, which iscancer cells and stabilizes cellular proteins includingases. In the SCLC cell line H69, geldanamycin inhibitedand functional expression of MET leading to reducedviability of four SCLC cell lines and increased apop-

In NIH3T3 cells expressing HGF or MET mutations,in down-regulated MET protein expression, inhibiteddentmotility and invasion, and blocked transformationine [115].eceptor interaction: Once the mature MET protein isthe plasmamembrane, its interactionswithHGF can bea number of ways, including competitive antagonismreceptor, antibody-mediated neutralizing of the HGFrevention of the generation of a mature HGF ligand./NK (stands for N-terminal hairpin domain and kringlecomprised of four variants of the alpha chain of HGF,one (NK1) to four (NK4) kringle domains. These pro-akMET agonists, and they act as competitive inhibitorsMET. They are effective in cells that possess paracrinee activation, but are not effective against intracellu-ivating mutations [116119]. Treatment of cancer cellK4 inhibited HGF-stimulated motility, migration andvitro. It inhibited tumor growth, invasion and dissem-ouse models including Lewis lung carcinoma, GB-d1

gall bladderbreast, andmore, in Lewmouse xenesis: Treatetumor cellsgrowth andinduced bymicrospherthe subcutawhich signiThis treatmthe numberof blood vesNK4wasalsand glioblas

ReceptocompetitiveHGF bindinsignaling. Tcell prolifeinduce tum

Similarlychain of HGtion of threepitopes ontumors depairpin RNA); miRNA(micro RNA); DNA (deoxyribonucleic acid); HSP(phosphate).

carcinoma, SUIT-2 orthotopic pancreas, MDA-MB-231PC-3prostate carcinomamodels [118,120124]. Further-is lung carcinomaand Jyg-MC(A)mammary carcinoma

ografts, it inhibited growth, metastasis and angiogen-d mice demonstrated increased numbers of apoptotic, decreased tumor microvessel density, and decreasedmigration of human microvascular endothelial cells-FGF, VEGF, HGF [122]. Recently, cationized gelatines incorporating NK4 plasmid DNA were injected intoneous tissueof Lewis lung carcinomamousexenografts,cantly prolonged the survival time period of the mice.ent also suppressed increases in the tumor volume andof lung metastatic nodules; it suppressed the numbersels and increased the number of apoptotic cells [125].o showneffective incolorectal cancer, pancreatic cancertoma cells [124,126,127].r-ligand interactions can also be modied non-ly. Soluble decoy receptors bind HGF and, antagonizeg to MET, and therefore inhibit MET dimerization andhey have been shown to inhibit HGF-dependent tumorration, survival, angiogenesis and metastasis and toor regression along with radiotherapy in mice [128]., the anti-HGF antibody binds an epitope in the betaF and prevents it from binding to MET. A combina-e mouse monoclonal antibodies (which bound threeHGF) blocked cell-scattering and morphogenesis in

endent on an autocrine MET-HGF loop [129]. AMG102

N.A. Cipriani et al. / Lung Cancer 63 (2009) 169179 175

(Amgen, Inc.) is a fully human IgG2 monoclonal antibody that bindsand neutralizes SF/HGF preventing its binding to c-MET and acti-vation of this pathway [117]. Recent interim analysis from a phase Iopen label dbyGordon eThe agent wmaximum tincludedgrasmall cell luand grade 3with advanplete) wereprogression[130].

AV-299 irently in eaPharmaceu

Anotherreceptor isinactive prnon-cleavabproteolyticusing lentivuncleavableactivation,expressionformation o

RTK inhismall moleis epitomizBcr-Abl in Coverexpressin certain Ntailored toget tumor calready beedrugs seem

One smtesting isautophosphsignaling intive in METlines with alines, it indautophosphstream targtranscriptiocarcinoma cphorylationphosphorylIn small celtion of p-ERp-RB, p-addbition p-PKmesothelioinhibited H

A secon(Pzer, Inc.)MPM. It bloPuri et al. sand found tPHA665752themice, annodules we[135]. Furth

rylation of MET and phosphorylation at the c-Cbl binding site inNCI-H69 and A549 cells. An antiangiogenic effect was also demon-strated, as PHA665752 treatment resulted in greater than 85%

ion itureP-1 (PHA6g gr

ing csingovedGF a, decleent[137

hirdtitivencermon2341atedNCaftecinoafts,xenospecGTL

sis, d, Akturthnicalin clile ins wimint ofdisescalar efed steekd fatarrhenctioas deled [80 (le taDGRe rec[141ptedcle antil dxims do02 sdoseitieslivermorvehileose escalation clinical trial in solid tumorswas reportedt al. At the time of report, 31 patients had been enrolled.as administered intravenously every 2 weeks with a

olerated dose of 20mg/kg. Dose-limiting toxicities seende3hypoxiaanddyspneaseen inonepatientwithnon-ng cancer and chronic obstructive pulmonary disease,gastrointestinal bleeding observed in another patientced pancreatic cancer. No responses (partial or com-observed, 13 patients had stable disease, 7 patients hadof disease, and 11 were not available for evaluation

s an anti-HGF antibody that targets SF/HGF, and is cur-rly development through a joint partnership of AVEOticals and Schering-Plough Pharmaceuticals [131].mechanism to prevent HGF from binding to the METvia uncleavable pro-HGF. HGF is usually cleaved fromo-HGF to active HGF. Mazzone et al. generated ale form by substituting a single amino acid in thesite. They locally delivered the uncleavable pro-HGFirus vectors in mice and found that substitution ofpro-HGF for normal HGF inhibited HGF-mediatedMET

tumor growth, angiogenesis and metastasis. Systemicinhibited the growth of transplanted tumors and thef metastases [132].bition: The inhibition of receptor tyrosine kinases bycules is already used in therapy of human tumors, anded by the following targeted therapies: imatinib forML and mutant c-Kit in GIST; trastuzumab in Her-2ing breast ca; bevacizumab in colorectal ca; getinibSCLCs [133]. These small molecule inhibitors can bereceptor tyrosine kinases in order to specically tar-ells. Their effectiveness in treating human cancers hasn demonstrated, and development of newRTK inhibitors promising.all molecule inhibitor currently undergoing in vitroSU11274 (Sugen, Inc.), and functions by blockingorylation of MET at sites required for downstreamcluding the P13K, AKT, mTOR pathways. It is effec--transformed or MET-activated cell lines, but not inctivated ABL, JAK2, PDGFR kinases [134]. In BaF3 celluced G1 cell cycle arrest and apoptosis, decreased METorylation and decreased phosphorylation of down-ets including AKT, GSK-3, and FKHR (a pro-apoptoticn factor) [134]. Specically in non-small cell lungell lines, it inhibited MET autophosphorylation, phos-of the c-Cbl binding epitope, andHGF-induced tyrosineation of cell proteins including S6K, AKT, ERK1/2 [59].l lung cancer, it inhibited HGF-stimulated phosphoryla-K2, p-ERK1/2, p-MEK1/2, p38, p-MAP kinase, p-AKT1,ucin and p-CREB, and it inhibited HGF-mediated inhi-C, p-PKC/ and p-CDK1 [99]. In malignant pleuralma, it decreased cell growth,motility andmigration andGF-induced signal transduction [65].d promising small molecule in inhibitor, PHA665752, has been shown effective in vitro in SCLC, NSCLC andcks phosphorylation of MET, AKT and p70-S6K [59].tudied the effects of PHA665752 in mouse xenografts,hat NCI-H69-derived SCLC tumor nodules treated withfor 3 weeks became clinically undetectable in 50% ofd tumor volumewas reduced by 99%. NCI-H441 NSCLCre reduced by 75% and A549 NSCLC nodules by 59%ermore, this small molecule inhibited autophospho-

reductvasculaand TS[135].reducininhibitexpresalso prMET/Hgrowthcell cydependERK1/2

A tcompelung cationdewith PFstimulhumanby 43%tric carxenogr(PC-3)84%, recinomaapoptoof MET

A fopre-clirentlymolecupatientapy. Adfor 2 oupoints:were eable foachievto 34 wincludeand diliver fudose wschedu

XL8molecuFLT3, Pals werIllinoisinterruday cydose uthe mapatientIn the 0erated3 toxiction inand tuseen in30%) wn CD31 staining, which corresponds to a reduction in. Similarly, VEGF (pro-angiogenic) was down-regulatedthrombospondin-1, anti-angiogenic) was up-regulated65752 was shown to cooperate with rapamycin byowth, inducing apoptosis and cell cycle arrest, andonstitutive cell motility of BaF3 TPR-MET- and METH441 NSCLC cells [136]. This small molecule inhibitoreffective in mesothelioma cell lines that exhibited a

utocrine loop (H2461 and JMN-1B lines). It inhibitedcreased in vitro cell migration and invasion, inducedarrest at the G1S boundary and induced a dose-decrease in phosphorylation of MET, p70S6K, Akt, and].small molecule, PF2341066 (Pzer, Inc.), is an ATP-inhibitor of MET kinase activity. In in vitro studies ofcell lines, NCI-H69 cells expressing the R988C muta-

strateddecreasedMETphosphorylation after treatment066, andNCI-H441 cells demonstrated decreasedHGF-migration and invasion [138]. In mouse xenografts ofI-H441 NSCLC cells, mean tumor volume decreasedr 38 days of PF2341066 treatment. Similarly, in gas-ma (GTL-16) xenografts, renal cell carcinoma (Caki-1)glioblastoma (U87MG) xenografts and prostate cancergrafts, tumor volume decreased by 60%, 53%, 97% andtively. Further studies of PF2341066-treated gastric car--16 cells demonstrated decreased mitosis, increasedecreased angiogenesis and decreased phosphorylation, Erk, PLC-1 and STAT5 [138].smallmolecule,ARQ197 (Arqule, Inc.) hasdemonstratedactivity against several human xenografts, and is cur-nical trials. It is an orally administered, selective smallhibitor of MET. It underwent Phase I testing in 38th advanced stage solid tumors who failed prior ther-istration was cyclic over 3 weeks: twice-daily dosing3weeks. Dosingwas continued until the following end-ase progression, unacceptable toxicity, or other. Dosested from 10 to 360mg/day. Thirty-three were evalu-cacy. Of these, two achieved a partial response and 19able disease. Average time to progression was from 10s. There was no dose limiting toxicity. Adverse eventsigue (24%) and GI symptoms such as constipation (21%)a (21%). Grade 3 toxicities seen included elevation inn enzymes seen in 3% of treated patients. The optimaltermined to be 120mg PO BID. Phase II trials are now139,140].Exelixis, Inc.) is another orally bioavailable smallrgeted to multiple RTKs, including MET, VEGF, c-Kit,F, Ron and Tie-2 [141]. Results of two phase I clinical tri-ently presented at the 2007 ASCO meeting in Chicago,,142]. The rst trial of XL880 (XL880-001) involved andosing schedule of 5 days on and 9 days off of a 14-nd the second (XL880-002) consisted of a xed dailyisease progression [141,142]. In the XL880-001 study,um tolerated dose was 3.6mg/kg with a total of 40sed and evaluated for safety and tumor response [141].tudy, 15 patients were accrued, and the maximum tol-was dened by the protocol to be 80mg/day. Gradeseen in the 001 study included asymptomatic eleva-function enzymes, palmar-plantar erythrodysesthesia,hemorrhage. Partial response (by Recist criteria) waspatients. Six patients had a minor response (less thansix patients had stable disease after 3 months [142].

176 N.A. Cipriani et al. / Lung Cancer 63 (2009) 169179

The XL880-001 trial was recently updated at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and CancerTherapeutics in San Francisco, CA [143]. At this update, 33 patientswere accruand tumor rhypertensiopatients haan early phgastric canc2007 AACR-of presentaactivating Msion was thrate was obable patientno grade 4

The thirical trials isRTKs includdemonstratsion of tumdose-escalalater updatence. At thmaximumand 40 patirespectivelytion enzymadverse eve4 patientsdemonstratlation is on

Other aginclude SGXinhibitor ofmulti-kinasMET, VEGFRin cell cultuilarly, HPK-MET kinasecompetitivemodulatestion and dis

MET pepcarboxy-terby bindingmigration aanti-MET anan antagonproliferatioagonist/ant

8. Conclus

The receof human csion ormutsurvival, another RTKsresearch inare similarlthe thorax,ciated withsearch for n

Conict of interest

None.

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portdatiApplcMuo to R

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mal Alin 20to J, Didemeill Hnce. Ottaro. Identcogen

i Renzpressncogenaldinictor anceptonnenowthchangll Bioadt F,e c-md. Nahmidt. Scattature 1arfatyet pro94;26moglol 200ng Wr/scatit Revristend cha05;22aPC,Ml for taulikpatocerapettler Mrgets imoglansduaestrifamilyowthndinorine 9iol Chellaet/Hermatio05;25trellidophc-MeubeyrN85-eceptodriguand

94;9:urnieatter oed with 24 and 22 patients being available for safetyesponse, respectively. Grade 3 toxicities observedweren, dehydration and confusion and a total of 10 out of 22d stable disease after 3 months [143]. Interim data fromase II trial of XL880 in papillary renal cell carcinoma,er, and head and neck cancer was also reported at theNCI-EORTC International Conference [144]. At the timetion, a total of 21 patients had been enrolled, 5 withET mutations and 16 with wild type MET. Hyperten-e only reported grade 3 toxicity. 100% disease controlserved in 15 out of 19 patients and 12 out of 16 evalu-s had stable disease after 6months. In all three studies,or 5 toxicities have been reported [144].d orally bioavailable small molecule undergoing clin-XL184 (Exelixis, Inc.). It is also targeted to multipleing MET, VEGFR2/KDR, KIT, FLT3, and Tie-2, and hased preclinical inhibition of tumor growth and regres-or in human xenografts [145]. Results from a phase Ition study was reported at the 2007 ASCO meeting anded at the 2007 AACR-NCI-EORTC International Confer-e time of update, 44 patients had been enrolled andtolerated dose had not yet been dened. A total of 38ents were evaluable for safety and efcacy reporting,. Grade 3 toxicities seen included elevated liver func-es and palmar-plantar erythrodysesthesia. One seriousnt included grade 4 pulmonary embolism. A total ofhad a partial response (2 conrmed) and 15 patientsed stable disease after 3 months of therapy. Dose esca-going [146].ents undergoing early phase and preclinical testing523 (SGX, Inc.) an orally bioavailable small moleculeMET in phase I dose escalation clinical trials and thee inhibitor MGCD265 (MethylGene, Inc.) that targets-1,2,3, Tie-2, and Ron RTKs. It has been investigatedre and is scheduled for clinical studies [147,148]. Sim-56 (MP-470) (Supergen, Inc.) inhibits c-Kit, PDGF and[149]. K252a is a staurosoporine analog and an ATP-MET kinase and serine/threonine kinase inhibitor that

wild type and mutant (M1268T) MET-dependent func-semination of tumor cells in vivo [150].tides are largemolecules derived from theMET receptorminal tail region which inhibit downstream signalingto MET and inhibiting HGF-mediated invasion, cellnd branched morphogenesis [151]. The monovalenttibody 5D5 (as well as its single arm version) acts asist and inhibits MET phosphorylation, HGF-dependentn and migration in vitro. The bivalent form acts as anagonist [152154].

ion

ptor tyrosine kinaseMET is implicated in awide varietyancers, including lung and mesothelioma. Overexpres-ation of this receptor or its ligand promotes cell growth,giogenesis, and metastasis. Targeted therapy againsthas already proven clinically benecial, and current

to therapy against MET and its downstream pathwaysy efcacious. By targeting theMETpathway in tumors ofwe hope to decrease the morbidity and mortality asso-lung cancer and mesothelioma, and will continue toew pathways and mechanisms for anti-tumor therapy.

Ackno

SupV-FounliomaKate MChicag

Refere

[1] JeJ C

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ed in part by NIH/NCI, American Lung Association,on (Guy Geleerd Memorial Foundation), Mesothe-ied Research Foundation (Jeffrey Hayes Memorial),llen Foundation, and Respiratory Health Association ofS.

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MET as a target for treatment of chest tumorsIntroductionMET structure and functionMET in tumorigenesisMET in SCLCMET in NSCLCMET in mesotheliomaTherapeuticsMET expression at the RNA levelMET expression at the protein level

ConclusionConflict of interestAcknowledgmentsReferences