Cell Line-based Platforms to Evaluate Anticancer Agents

7/28/2019 Cell Line-based Platforms to Evaluate Anticancer Agents

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Th discy and dnt f ffcti cancdicins has histicay bn had by th ack fiaby dicti cinica ds t assss th tha-tic fficacy f candidat agnts. Sch ds haagy cnsistd f han t-did c insagatd ith in ct as xngafts in ic,and cnty f gnticay ngind s d-s f han tignsis. Athgh th hysigicaanc f ach f ths ds as w as thi s-fnss f assssing dg fficacy ain cntsia,and ach aach is assciatd with itant caats,st instigats ag that ths ain bst, andssiby ny ts f th idntificatin and chaacti-zatin f dicina agnts that can tntiay dccinica bnfit in canc atints.

T-did c ins ha bn sd f anyyas as dg discy ts (Timeline). Hw, it is nycnty that instigats ha bgn t aciat th

ns dg f gnic htgnity acssth han canc atint atin, and thfacss t-did c ins, and th ccia that this disity has in th aiab cinica sns ttatnt. This aizatin has inigatd fftst xit ths ins f th distinct s f catinggntysns atinshis. Th aidy xandings f canc c ins t dict th cinica fficacy fnw agnts is aady affcting th cs f dg d-nt and is nw bcing an itant t f thbitchngy and haactica indstis, in whichffts that a fcsd n cay tagtd cancthais a accating.

In th fwing sctins, w iw th aicatinf canc c ins t th discy and aatin ftntia nw anticanc agnts. W as dscib thatiy cnt s f ag c in ans t catth gnic disity f han canc, with th ga fidntifying biaks that ight aw th statifica-tin f atints f aiat dg tatnt. W asca sch aachs t th ais th cini-ca d systs that a cnty bing xd taat canc dg fficacy.

Hiti pptivTh stabishnt f th Natina Canc Institt 60(NCI60) atf (BOX 1;Timeline), th fist high-thght canc c in scning ga f itskind, was a scintific tour de force that qid th d-nt f any nw tchngis, sch as th d-nt f assays f asing cyttxicity, intdctin

f iniatizatin in th f f icats, ata-tin f iqid handing and high data anaysis nan ncdntd sca (iwd in Ref. 1). Th tch-ngis dd as a dict st f this gaain th cnstns f any canc dg-scninggas tday and wi baby ain s f thfsab ft. Hw, as dscibd bw,th iitatins isd by th s f ny 60 c insha bc incasingy aant in cnt yas.

Th dcisin t s 60 c ins has t b cnsiddf th scti that in th id f 1984 t2005, ding which th dnt, inta-tin and s f th NC160 ga was in ffct,

Center for Molecular

Therapeutics, Massachusetts

General Hospital Cancer

Center and Harvard Medical

School, 149 13th Street,

Charlestown, MA 02129,

USA.

Correspondence to J. S.

email: [email protected].

harvard.edu

do:10.1038/rc2820

Pubhd o

19 march 2010

Cell line-based platforms to evaluatethe therapeutic efficacy of candidateanticancer agentsSreenath V. Sharma, Daniel A. Haber and Jeff Settleman

Abstract | Efforts to discover new cancer drugs and predict their clinical activity are limited by

the fact that laboratory models to test drug efficacy do not faithfully recapitulate this complex

disease. One important model system for evaluating candidate anticancer agents is humantumour-derived cell lines. Although cultured cancer cells can exhibit distinct properties

compared with their naturally growing counterparts, recent technologies that facilitate the

parallel analysis of large panels of such lines, together with genomic technologies that define

their genetic constitution, have revitalized efforts to use cancer cell lines to assess the clinical

utility of new investigational cancer drugs and to discover predictive biomarkers.

models of cancer

REVIEWS

NATure revIeWS |CanCer volume 10 | AprIl 2010 |241

20 Macmillan Publishers Limited. All rights reserved10
mailto:[email protected]:[email protected]:[email protected]:[email protected]


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Oncogene addiction

Th hypoth that tuour

arg a a rut o a partcuar

ocogc o ra

dpdt o th cotud

xpro o that ocog.

Oncogenic shock

A cha to xpa

ocog addcto, whch

acut actvato o a

ocoprot aocatd wth

drta attuato rat o

pro-urvva ad pro-apoptotc

ga aatg ro th

ocoprot, uch that

apoptotc ga bco

prdoat ad k th

cacr c.

Synthetic lethality

Two g ar ythtc tha

utato o thr o o th

two g copatb wth

vabty but utato o both

g rut c thaty.

Lineage addiction

Th trct rqurt or

crta ag-pcc g

tuorg (or xap,

aocyt-pcc g

aoa).

Non-oncogene addiction

Cacr c ght harbour

potta thraputc targt

that do ot corrpod to

ocog but cottut

prot to whch th cacr

c ary addctd.

th ainstay f canc tatnt agy cnsistd fnnscific cyttxic agnts, st f which shwds actiity in a cnsidab tin f tatd can-c atints210(TABle 1). Gin th high ats f cinicasnss that w bsd (2570%), it wd b a-snab t ass that th 69 han t-didc ins sntati f ach canc that cis thNCI60 an wd b adqat t cat sch fqn-cis f dg sns. Hw, with th cnt adntf s-cad atinay tagtd anticanc thatics,cinica actiity is ftn iitd t sa sbsts f tatdatints, nding th csitin f th NCI60 answhat inadqat f th task f cating sch wfqncy snss. Sch anachnistic citicis nt-withstanding, it is fai t say that th NCI60 gawas ky t stabishing c in-basd scning at-f tchngis as a fndatin f anticanc dgdiscy and dnt ffts.

Gi htgity thputi

Th adnt f atinay tagtd thatics, aticay

ths dictd against ncgnic kinass, has std in anw gnatin f anticanc agnts with fw sid ffctsand issi cinica actiity. Hw, thi s in thcinica stting has ad that, as with th taditinacyttxic chthay agnts, th cinica sns ttatnt with ths agnts ais sbstantiay btwnatints n ang ths with histgicay indis-tingishab disas. This is aticay w xifidin th cas f tysin kinas inhibits (TKIs) that tagtida gwth fact ct (eGFr) (TABle 2). Ths,sns t th cinicay ad eGFr TKIs, gfitinib(Issa; AstaZnca) andtinib (Taca; Gnntch/oSI phaacticas), is stictd t and 10% f

atints with nn-sa-c ng canc (NSClC)1115.Siiay, tinib, which has as bn uS Fd andDg Adinistatin (FDA)-ad (in cbinatinwith gcitabin (Gza; liy)) f th tatnt fchthay-nai cay adancd and tastaticancatic cancs, shws a inia incas in bjctisns at f 8.6% (cad with 8.0% f gcitab-in and a acb)16 (iwd in Ref. 17). ony and9% f atints with chthay-facty cctacanc and 13% f atints with had and nck canc,which xss eGFr, snd t a thatic n-cna antibdy dictd against th ct (ctxiab(ebitx; Bistmys Sqibb/mck/ICn SystsIncatd))18,19 (iwd in Ref. 20). Siia snsats f ~10% w bsd with an atnati eGFr-tagting antibdy, anitab (vctibix; Agn), intastatic ccta cancs21.

Bynd eGFr, iitd cinica sns t TKIstagting th t-assciatd kinas athways is acnt th in ns canc sttings (TABle 2) asxifid bytastzab(Hctin; Gnntch)22,23,

aatinib (Tykb; GaxSithKin)24,25, safnib(Nxaa; Bay HathCa/onyx phaacticas)26,27,snitinib (Stnt; pfiz)28,29 and bacizab (Aastin;Gnntch). Bcking this tnd, iaiy in chnicyid kaia (Cml), a TKIs sch as iatinib(Gc; Natis), dasatinib (Syc; BistmysSqibb) and nitinib (Tasigna; Natis), which icitsnss in a ag tin f tatd atints,aanty fcting th ag tin f atintswh ha gnic sins affcting th dg tagt inCml3034. This ight as b t f BRAFkinas ta-tins, which cc in axiaty 7% f han can-cs, bt fat innty in anas (70%)35; itis anticiatd that BrAF inhibits wi id cinicabnfit in this atica stting.

It has bn sd that th cinica sns t ta-gtd TKIs tntiay fcts a stat focog addctothat aiss at a w fqncy in scific disas sttings36,37.In ths ncgn-addictd cancs, th act inhibitinf th nctin by th tagtd inhibit ay indcocogc hock, a tansint ibaanc in -sia and-attic signas acty fwing kinas inhibitin,sting in th dath f th canc c38,39. Atnatihythss t xain th scific dath f ncgn-addictd canc cs aft act inactiatin f th di-ing ncgn incd ythtc thaty40, ag addcto41and n o-ocog addcto42. B that as it ay, th

gnay bsd acity f cinica sns t tagtdthatics ndscs th gnic htgnity thatis inhnt in canc and stngy ags f gat -sntatin f c ins did f ais cancst adqaty cat this gntic disity, which ss tndi ch f th aiab sns t TKI thay.

c i p ug piig

Rationale. Th xinc with gfitinib and tinibhas taght s that, athgh ct tysin kinass(rTKs) sch as eGFr a itant tagts f tha-tic intntin, thi inhibitin ay b cini-cay fficacis in a sa sbst f atints ny, and

at g

Human tumour-derived cell lines have historically had a very important role in the

discovery and development of new cancer therapeutics.

The National Cancer Institute 60 (NCI60) platform, which introduced the concept

of high-throughput cell-based profiling, was crucial not only to the development of

technologies that are still being used in various high-throughput discovery platforms,

but also to the discovery of several agents that have subsequently been found to

demonstrate therapeutic efficacy.

Subsequently developed genomic analysis technologies have provided an

opportunity to link variable treatment responses to specific underlying genotypes,

highlighting the enormous genomic heterogeneity in human cancer and its role in

the response to therapy, and revealing the need to reconsider the scale of cell

line-based studies to assess the activity of candidate anticancer agents.

Consequently, much larger panels of cancer cell lines are beginning to be exploited

for the purpose of identifying genomic determinants of drug sensitivity, and several

studies have validated the usefulness of this approach to reveal clinically informative

biomarkers.

This development, together with additional technological developments involving

various three-dimensional culture systems and more sophisticated xenograft models,

has recently reinvigoratedthe application of cancer cell lines to the analysis of drug

efficacy in cancer.

Although throughput, as well as the physiological relevance of some of theseapproaches, remains a limitation of these systems, there seems to be little doubt that

tumour-derived cell lines will continue to have a vital role in the preclinical

assessment of new candidate anticancer agents.

R E V I E W S

242 | AprIl 2010 | volume 10 www.tu.com/iws/cc

http://www.uniprot.org/uniprot/P00533http://www.cancer.gov/drugdictionary/?CdrID=43649http://www.cancer.gov/drugdictionary/?CdrID=38428http://www.cancer.gov/drugdictionary/?CdrID=38428http://www.cancer.gov/drugdictionary/?CdrID=657337http://www.cancer.gov/drugdictionary/?CdrID=42384http://www.cancer.gov/drugdictionary/?CdrID=37857http://www.cancer.gov/drugdictionary/?CdrID=42265http://www.cancer.gov/drugdictionary/?CdrID=269659http://www.cancer.gov/drugdictionary/?CdrID=299013http://www.cancer.gov/drugdictionary/?CdrID=299061http://www.cancer.gov/drugdictionary/?CdrID=43234http://www.cancer.gov/drugdictionary/?CdrID=37862http://www.cancer.gov/drugdictionary/?CdrID=315885http://www.cancer.gov/drugdictionary/?CdrID=435988http://www.ncbi.nlm.nih.gov/gene/673?ordinalpos=4&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene/673?ordinalpos=4&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.cancer.gov/drugdictionary/?CdrID=435988http://www.cancer.gov/drugdictionary/?CdrID=315885http://www.cancer.gov/drugdictionary/?CdrID=37862http://www.cancer.gov/drugdictionary/?CdrID=43234http://www.cancer.gov/drugdictionary/?CdrID=299061http://www.cancer.gov/drugdictionary/?CdrID=299013http://www.cancer.gov/drugdictionary/?CdrID=269659http://www.cancer.gov/drugdictionary/?CdrID=42265http://www.cancer.gov/drugdictionary/?CdrID=37857http://www.cancer.gov/drugdictionary/?CdrID=42384http://www.cancer.gov/drugdictionary/?CdrID=657337http://www.cancer.gov/drugdictionary/?CdrID=38428http://www.cancer.gov/drugdictionary/?CdrID=43649http://www.uniprot.org/uniprot/P00533


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that actiating tatins in th gns ncding thsrTKs cnstitt n f th sf dicts f cinica

sns t TKIs (iwd in Refs 43,44). Hw, asdiscssd ab, th sa tin f tatd atintswh bnfit f TKIs ints t th gntic ht-gnity that is a chaactistic f canc and highightss dficincis in th cnty sd c-basd dgscning atfs as ts f discing biak-s that dict cinica sns. F xa, a sicacatin as that t caitat th 10% snsat t eGFr TKIs sch as gfitinib tinib, a c-basd scn wd qi a ini f 10 and id-ay >100 diffnt NSClC-did c ins. A siiacas cd asiy b ad f a t tys, sggst-ing that an idaizd han t c in fiingan shd cnsist f 2,0006,000 c ins (assingcnsatiy that th a 20 diffnt tiss iginswith qa sntatin). This is bynd th caac-ity f cnty aaiab c-basd scning atfs.o wn sach f han t-did c insin a bicy aaiab sitis sggsts that thtta nb f ant c ins is and 1,500 t2,000. Gin th cnt c-basd scning stat-gis (f xa, NCI60) that tyicay in a sanb f c ins (ss than 10) sntati f acht ty, it is niky that snsitiity t dgs schas gfitinib tinib (which yid snss in ~10%f NSClCs) wd ha bn inkd t a cini-cay ant dg-snsitizing gnty. Thf, w

sggst that c in-basd dg scning atfsshd iday b dsignd with th caacity t dtctsnss in th 110% ang in a atica canc tyand shd adqaty snt th gntic htg-nity f canc. Athgh in vitro anaysis f ctdc ins is ctainy assciatd with caats atd tffcts tntiay attibtd t a nn-hysigica ni-nnt and ng-t assag in ct, cnt find-ings dnstating that t-did c ins agytain th gnic fats f th iay t 45,46fth bst th aidity f this aach in nc-ing cinicay aningf catins btwn tc gntics and dg snsitiity.

Th cmT1000 pt

With this ga in ind, a han t c in atf

with as bad a sntatin as ssib was cntystabishd, which cnty incds 1,200 c ins.This an f c ins is fd t as th Cntf mca Thatics 1000 (CmT1000), as aniica dtinatin f thi tis sggststhat ny ~80% f sch ins a anab t fiingf dg snsitiity, agy fcting tchnica iita-tins sch as insfficint dbing tis atyica c-t qints. This atf is nw bing sd tb th gntic basis f snsitiity t ad andinstigatina anticanc agnts.

Methodology and early findings. Dtais f th thd-gis sd in th CmT1000 canc c in-basd scn-ing atf ha isy bn td47. Bify,this fiing atf ins a 72-h assay f csatd n astic nd standad ct cnditins tdtct changs in c nb as a cnsqnc f tat-nt with ais xinta agnts. Snsitiity fi-ing with this atf cncd in may 2006 and, asf may 2009, 127 candidat and stabishd anticancagnts ha bn intgatd f cytstatic and/ cyt-txic actiity against axiaty 700 han t-did adhnt c ins, catiy csndingt and 70,000 dgc in aiings.

on f th ay siss that gd f thisag data st was th akab dg t which han

t-did c ins caitat cinica findings,bth qaitatiy and qantitatiy, with gad t thisns t tagtd inhibits. eay stdis adthat th snss f c ins t agnts tagting tinkinass w highy stictd, and c ins with xqi-sit snsitiity t eGFr, Her2, meT, att-didgwth fact ct (pDGFr), anaastic yhakinas (AlK) BrAF kinas inhibits w tyicayakd by actiating tatins aificatin f thgn ncding th dg tagt. In st cass, sch ta-tins w catd with atica t tys (fxa, EGFR tatins in and 10% f NSClC);athgh, a c ins did f th t

Timeline | Hity th vpt -i pt vutig ti gt

1950 1951 1955 1963 1977 1986 1989 1990 1992 1995 1997 1998 2000 2006

HeLa: first human

cell line developed

from a cancer

patient

Animal cell

culturebecomes

routine

Culturinghuman tumour

cells as MCTS

Clustered heat

maps reportedCell-free cell culture

media developed

DTP established156

DTPexternal

review

CMT1000

launched

COMPARE

algorithm

reported

(2000present)

NCI60 operates

as service screen

for drug profiling

Methods for

cryopreservation of

mammalian cells

developed

(19861990)

NCI60 model

development

Culturing

human tumour

cells in PVDFhollow fibres

Human tumour cell lines

retain genomic features of

the primary tumour from

which they were derived

(19902000)

NCI60 as a

drug discoveryscreen157,158

JFCR39

launched

National Cancer Institute (NCI)-related events are indicted with blue boxes; Center for Molecular Therapeutics (CMT)-related events are indicated with red boxes.DTP, Developmental Therapeutics Program; JFCR, Japanese Foundation for Cancer Research; MCTS, multicellular tumour spheroids; PVDF, polyvinylidene fluoride.

R E V I E W S


http://www.uniprot.org/uniprot/Q9UM73http://www.uniprot.org/uniprot/Q9UM73


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Clustered heat map

A data atrx dpay whchth vau o a varab a

two-doa ap ar

rprtd a coour.

COMPARE algorithm

A coputr progra, whch

copar th pattr o drug

tvty, a rvad by th

nCi60 aay, to a tt

copoud wth th tvty

pro o a drug prvouy

ttd agat th nCi60

pa. Drug wth ar c

tvty pro td to

hav a ar od o acto.

tys (f xa, gastic cancs) w as fnd thab th sa gntic sin and xhibit snsitiityt that atica inhibit 48. Thf, gnticaydfind canc sbsts, iscti f th tiss f igin,s t b assciatd with sns t scific kinasinhibits, highighting th tntia bnfit f thstatificatin f atints basd n gnty, ath thann tiss f igin, as is cnty th standad acticin dica ncgy.

Th bsatin that scific gntys a tightyassciatd with dg snsitiity was fth xd inth cntxt f NSClC, and sing th CmT1000 at-

f, snsitiity t an AlK inhibit was w catdwith AlK-actiating chsa tanscatins thatais at w fqncy (37%) in ths ts4951.Siiay, sing th CmT1000 atf, an NSClCc in with snsitiity t a pDGFr kinas inhibitwas fnd t hab c-aificatin f gns ncd-ing th ct (pDGFrA) and n f its igands(pDGFC)52. pDGFrA is actiatd in axiaty13% f NSClCs53. Thf, it is ssib t sbdiidNSClCs int gnticay disct sbsts n th basis fth actiating tatins that thy hab, and achf ths sbsts ay csnd t atint chtsthat a iky t bnfit f tatnt with scific

inhibits that tagt th dcts f ths scificgntic sins (BOX 2). A siia aach cd bbady aicab in a wid aity f han cancs,thby snting a aadig shift f th cntaach t aating and tating canc atints.

Hiachica csting anaysis f snsitiity fisthat g f th CmT1000 c in scn can asa nanticiatd atinshis btwn distinct inhib-its. Cnctay, this is anags t th COmPAReagorth and this aach has bn sd t ca14 diffnt kinas inhibits n th basis f thi acti-ity against 500 han t-did c ins. Schan anaysis can a nanticiatd siiaitis btwncnds with tatiy distinct tagts48.

on f th cnnts f th Canc Gnpjct at th Wc Tsts Sang Institt, uK, isth Cacr C l Projct, a aj -sqncing fftthat is fcsd n th st cn canc-assciatdgns in han t-did c ins. T dat, thisnging fft has d t th -sqncing f 51 cancgns in 785 han t-did c ins, yid-

ing a ich databas f tatins in cn ncgnsin han canc c ins (dtais f th gns and thc ins that a at f this databas can b fnd atth Canc C lin pjct wbsit; s Fth inf-atin). A ag tin f han t c insin th CmT1000 a sntd in th Canc C linpjct and ffts a ndway t incd a f th cins in th CmT1000 in th Sang Institts CancC lin pjct. Thf, it is nw ssib t bgint intgat tatina infatin that is assciatdwith ths c ins with dg snsitiity data in an fftt btt ndstand th gnic dtinants f cinicasns t ais canc thatics.

In additin t th gnic htgnity sntacss ts f diffnt atints, it is bcingincasingy idnt that htgnity f c tys int c atins is as iky t ha an i-tant in dg snsitiity. F xa, t csbsts xhibiting distinct stats f diffntiatin st c tis, can ha distinct dg snsitiity(iwd in Refs 54,55). m, ctd canc cins, as w as t cs f atints, can xhibitsch htgnity, and in vitro stdis ha ad thatsch c htgnity can affct th sns t tat-nt with anticanc agnts (iwd in Refs 5658).Athgh tyica sht-t tatnt assays a iky tyid adts that a nt affctd by th tntia s-

nc f a sa sbatin f cs with distinct dgsnsitiity, sch htgnity cd ctainy cntibtt th nat f cinica tatnt snss in atints.

aiti ppiti i p

Tissue-specific cell line panels. oth stdis hasd sa canc c in ans cnsisting ithf sht-t t-did cts stabishdc ins t caitat th gnic disity f can-c. Sch stdis sing 51 bast canc c ins 45,101 ana-did c ins59 and 84 NSClC cins46 achd th sina cncsin that th gnticandsca f t-did c ins is akaby

Box 1 | Th ncI60 Jfcr-39 ig pt

nCI60

Launched in 1990, the National Cancer Institute 60 (NCI60) platform consists of 60

human tumour cell lines, representing 9 cancer types; namely, leukaemia (represented

by 6 cell lines), melanoma (8 lines), cancers of the lung (9 non-small-cell lung cancer

lines), colon (7 lines), brain (6 lines), ovary (7 lines), breast (6 lines), prostate (2 lines) and

kidney (8 lines)130. However, recent advanced genetic techniques have revised the

number of unique cell lines in the NCI60 panel to 57. Details regarding the NCI60screen can be found at theDevelopmental Therapeutic Programwebsite (see Further

information). Since 1997, the NCI60 programme has been a compound evaluation

resource for the research community. An in-depth review of the NCI60 programme has

previously been published1. One of the first revelations to emerge from the NCI60

screening programme was that drugs with similar profiles of cell line sensitivity tend to

function through a common mechanism, a finding that led to the development of the

COMPARE algorithm131. This algorithm enabled the rapid comparison of newly

screened compounds with previously screened compounds to determine whether the

compound exhibited a new or previously described mode of action. In the early 1990s,

gene expression information was integrated with the screening data, resulting in the

development ofcutrdhat ap132135. Such studies revealed that the broad

chemotherapeutic resistance of several cell lines in the NCI60 panel was strongly

correlated with the expression of multidrug resistance 1 (MDR1; also known asABCB1),

which encodes a P-glycoprotein136. During the 1990s several new anticancer agents

were identified by the NCI60 screening programme137

, most notably bortezomib, whichwas approved by the US Food and Drug Administration for the treatment of multiple

myeloma138,139. As of 2005, approximately 88,000 pure compounds and 34,000 crude

extracts have been screened against the NCI60 panel140. Given this high throughput,

the NCI60 represents a true drug discovery platform (as opposed to a drug

development tool).

JFCr39Building on the NCI60 experience, researchers at the Cancer Chemotherapy Center of

the Japanese Foundation for Cancer Research (JFCR) established the JFCR-39 in 1999. It

is a panel of 39 human tumour-derived cell lines that included a subset of the NCI60

cell lines as well as additional cell lines derived from gastric cancer (owing to its

prevalence in the Japanese population)141. Using the COMPARE algorithm and

advanced data mining techniques this platform has been successful in identifying

several new anticancer agents142146 as well as tumour biomarkers147.

R E V I E W S


http://www.uniprot.org/uniprot/P16234http://www.uniprot.org/uniprot/Q9NRA1http://www.sanger.ac.uk/genetics/CGP/CellLines/http://dtp.nci.nih.gov/index.htmlhttp://dtp.nci.nih.gov/index.htmlhttp://dtp.nci.nih.gov/index.htmlhttp://dtp.nci.nih.gov/index.htmlhttp://www.sanger.ac.uk/genetics/CGP/CellLines/http://www.uniprot.org/uniprot/Q9NRA1http://www.uniprot.org/uniprot/P16234


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Cancer Cell Line Project

A projct wth th Cacr

Go Projct, t ocud

o gtc charactrzato o

a hua cacr c

currty ud aborator.

Th aay cud o o

htrozygoty ad copy

ubr aay, dtcto o

croatt tabty ad

dp rqucg o a

kow cacr g. Currty,

th projct vov 784 c

ad 51 o th ot

coo cacr g.

siia t that f th iay ts f which thyiginatd, iying that ctd t-did c

ins a aid gntic sgats f ts in vivo. Inadditin, ths stdis ad sa dg-snsitizinggntys; f xa, fibbast gwth fact c-t (FGFR)-actiating tatins w assciatd withsnsitiity t meK inhibits in anas59, ERBB2gn aificatin was inkd t snsitiity t tastz-ab in bast canc cs45 and KRAS tatins wfnd t assciat with snsitiity t HSp90 inhibitsin NSClC46, fth sting th s f canc cins t nc gntys that tntiay dict dg

nabiitis60.

Systems approaches. on f th st itant cha-ngs in diing biaks that a assciatd withdg snsitiity is th intgatin f data f th

ais systs atfs that yid gnic, tan-scitic, tic and ignic infatint stabish ca signats that ay b cini-cay sf. Sch signats ight b sf f bthdicting dg snsitiity in tatd atints andcidating chaniss f dg actin. T this nd,systs bigy aachs ha bn aid t an-s f c ins did f a atica t tyt disc aningf ca cats f dgsnsitiity. Sch an intgatd anaysis f 30 bastcanc c ins shwd that xssin f pAK1cnfs hysnsitiity t meK inhibitin61. T

c kiing by inhibitin f meK in bast canc cswas antagnizd by cncitant actiatin f th pI3Kathway, sggsting that in this stting th da inhibi-tin f meK and pI3K ight b fficacis thaninhibitin with sing agnts62. A siia systs anay-sis aach sing 48 bast canc c ins yiddan xssin signat f 13 gns that was assci-atd with th snsitiity f ths cs t th yainanag pG-11047, an instigatina cinica c-nd63. Sch stdis highight th tntia a fsysts aachs t intgat cx cainfatin that dscibs ca stats that a ass-ciatd with dg snsitiity sistanc t idntify

dicti biaks f cinica actiity, and ssibyt gain insights int th chanis f actin f ss

w-chaactizd agnts.

Synthetic lethality. T-did c ins ha asbgn t b sd t idntify gns that a in a synthtictha atinshi with actiatd ncgns (f xa-, tatd KRAS) distd t ssss(f xa, 53) in canc cs. Sch ffts hacnty yidd sa nw candidat thatic ta-gts that ain t b aidatd in atints6469. Siiay,t-did c ins ha as bn sf dsin th finnt f th tntiay itant tha-tic tagts, as ad thgh chanistic stdis fhnna sch as nn-ncgn addictin and inagaddictin41,42.

Drug combinations. exct in a cass, nthaywith anticanc agnts is nt cati and st c-nty sccssf anticanc thatic statgisin a cbinatin f dgs. Cbinatin ch-thay was fist sd in th tatnt f kaiasand yhas, bt has nw bn xtndd t thtatnt f sid ts. Athgh th ay cini-ca dnt f cbinatin tatnt statgiswas ainstakingy sw, ining tia-and- inatints, cnt innatins ha nabd th s fc in-basd scning atfs t x cbi-natia sac in a high-thght fashin. In n

stdy, 600 FDA-ad dgs w cbinati-ay anaysd (yiding axiaty 100,000 c-binatins) f gwth inhibity actiity against nhan ng t-did c in, A549 (Ref. 70).Sch an nbiasd in vitro anaysis ad nantici-atd syngistic intactin btwn dgs that asd in th tatnt f natd disass, and nf ths cbinatins was tstd and shwn t bacti in vivo sing A549 cs gwn as xngafts innd ic70,71. Athgh this stdy dnstats thfasibiity f this aach sing n han t-did c in, sch an ndtaking n a agan f han t-did c ins wd b

Table 1 |rp t bt vi t it Us fda-ppv hthputi gt

US FDappod chmothputic Goup Cc d spos ts rfs

Cyclophosphamide Alkylating agent 67% for ovarian cancer and 69% for breast cancer 9,10

Cisplatin Alkylating agent 67% for ovarian cancer and 47% for breast cancer 2,6

Carboplatin Alkylating agent 24% for ovarian cancer and 53% for breast cancer 8,9

Docetaxel (Taxotere; Sanofi Aventis) Mitotic inhibitor 31% for ovarian cancer and 39% for breast cancer 8,9

Vinorelbine Mitotic inhibitor 30% for ovarian cancer and 4160% for breast cancer 5,7

Paclitaxel (Taxol; BristolMyers Squibb) Mitotic inhibitor 42% for ovarian cancer and 27% for breast cancer 6,9

Gemcitabine (Gemzar; Lilly) Antimetabolite 49% for ovarian cancer and 36% for breast cancer 9,10

Fluouracil Antimetabolite 36% for breast cancer 4

Doxorubicin Anthracycline 61% for ovarian cancer and 45% for breast cancer 9,10

Etoposide Topoisomerae II inhibitor 48% for ovarian cancer and 26% for breast cancer 3,10

Topotecan (Hycamtin; GlaxoSmithKline) Topoisomerase I inhibitor 14% for ovarian cancer 10

FDA, Food and Drug Administration.

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nnta, abit thticay ssib. Gin thcnt stat f th tchngy this is sti ny a hbt it is iky that tchnica adancs in th ftcd nab sch an abitis nda. It is cathat xing a ssib dg cbinatins is i-tay issib, bt f nw, caying t sch ananaysis n iitd sts f cbinatins f whichth is a scintific atina is nt ny fasib btwd as b inaab in th dnt f ffcti thatic statgis f canc tatnt.Th abiity t x cbinatia sac with ag

nbs f han t c ins wd b n fth gatst changs f th ft, bt n whichiss t yid ich wads.

mig ug it i i

on f th aj iitatins t th cinica bnfitdid f canc dg thais is th bf aidy acqid dg sistanc. Thf, stcanc atints wh dnstat a sns t dgthay, wi ntay and ftn aidy aswith dg-sistant disas. Thf, it is itant

Table 2 | objtiv p t i ptit t it Us fda-ppv ki ihibit

US FDappodis ihibito

Tgt Cc Objctispos ts

rfs

Gefitinib (Iressa;AstraZeneca)

EGFR Non-small-cell lung cancer 919% 11,12

Erlotinib (Tarceva;Genentech/OSI

Pharmaceuticals)

EGFR Non-small-cell lung cancer 10% 15

EGFR Pancreatic cancer(in combination withgemcitabine (Gemzar; Lilly))

8.6% (comparedwith 8% withgemcitabine andplacebo)

16

Cetuximab (Erbitux;BristolMyers Squibb/Merck/ImCloneSystems Incorporated )

EGFR Advanced squamous cellcarcinoma of the head andneck

13% 19

EGFR Metastatic colorectal cancer 9% 18

Panitumumab(Vectibix; Amgen)

EGFR Metastatic colorectal cancer 10% 21

Trastuzumab(Herceptin; Genentech)

ERBB2 ERBB2-overexpressingmetastatic breast cancer

1526% 22,23

Lapatinib (Tykerb;GlaxoSmithKline)

ERBB2 Trastuzumab-refractorybreast cancer

39% 25

Sorafinib (Nexavar;Bayer HealthCare/Onyx Pharmaceuticals)

RAF1, VEGFR1,VEGFR2,VEGFR3 andPDGFRb

Advanced renal cellcarcinoma

10% 26

Unresectable hepatocellularcarcinoma

2% 27

Sunitinib (Sutent;Pfizer)

VEGFR1,VEGFR 2,VEGFR3,PDGFRbandRET

Advanced renal cellcarcinoma

31% 28

Imatinib-intolerantgastrointestinal stromaltumour

7% 32

Bevacizumab (Avastin;Genentech)

VEGFA Metastatic colorectal cancer 3% ECOG E3200 study(bevacizumab

monotherapy group)

Glioblastoma 2026% NCI 06-C-0064E andAVF3708g studies

Imatinib (Gleevec;Novartis)

BCRABL,PDGFR and KIT

Ph+ CML and Ph+ AML 76% 30

BCRABL,PDGFR and KIT

Metastatic or unresectableKIT+ gastrointestinal stromaltumour

3854% 31,32

Dasatinib (Sprycel;BristolMyers Squibb)

ABL, SRC, KITand PDGFR

Imatinib-intolerant orImatinib-resistant Ph+ CML

52% (majorcytogeneticresponse)

33

Nilotinib (Tasigna;Novartis)

BCRABL Imatinib-intolerant orimatinib-resistant Ph+ CML

47%(haematologicalresponse)

34

AML, acute myeloid leukaemia; CML, chronic myeloid leukaemia; EGFR, epidermal growth factor receptor; FDA, Food and DrugAdministration; PDGFR, platelet-derived growth factor receptor; Ph+, Philadelphia chromosome positive; VEGFA, vascularendothelial growth factor A; VEGFR, VEGF receptor.

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EGFR

Sunitinib

Oncogene

NSCLC (139 lines)

Effective inhibitor

ALK

MET

PDGFR

ROS

PF-2341066

TAE684

Gefitinib or erlotinib

CEL-1869

KRAS None

ERBB2

BRAF

PIK3CA

MEK1

PLX4032

Lapatinib (GW572016)

AZD6244 or PD-325901

GDC-0941

t d a btt ndstanding f th cachaniss ndying acqid dg sistanc.on f th xinta statgis that has bn sc-cssfy sd t addss this iss ins th sf dg-snsiti canc-did c ins as a df stabishing chaniss f acqid dg sist-anc. By cntinsy xsing sch dg-snsitics t tatnt in vitro a id f ti, it isftn ssib t iinat th ajity f cs whiscting f th xansin f atiy a dg-sistant cns. By caing ais tis fth anta dg-snsiti cs and th sctd dg-sistant cs, it is ssib t idntify scific c-a chaniss f dg sistanc. This aach hasbn sccssfy sd, f xa, t stabishMETaificatin as a chanis f acqid sistanct eGFr kinas inhibit thay in nn-sa-cng canc72, and CrAF xssin as a tn-tia chanis f acqid sistanc t BrAF inhib-it thay in anas73. In bth f ths cass,sch chaniss f acqid dg sistanc ightas ndi s cass fde novo dg sistanc,

aising th ssibiity that anags ffts t dacqid dg sistanc in ag ans f c inswith stabishd dg snsitiity cd as b sff idntifying additina chaniss fde novo dgsistanc.

Limitations and perspective. Th gistica changsassciatd with th ct and snsitiity fiingf ag canc c in ans cnsidaby iitsth thght f th atf with sct t thnb f cnds that can b aisticay tstdin a gin ti id. Cnsqnty, nik th NCI60atf, which has idd a syst f a atiy

high-thght anaysis f a ag nb f candidatagnts, th caatiy w thght f th chag c in atfs is sitd t fnctin as adg dnt t, agy t id infatinabt th actiity f a ch sa nb f w-chaactizd agnts that ha aady dnstatdis as candidat anticanc agnts. As with a cin-basd scns ining ncts, anthiitatin f sch anaysis is that ny c atn-s snsitiitis t tstd cnds can b scd,and s agnts that tntiay fnctin t affct thintactin f t cs with thi ninnt(f xa, angignsis inhibits inhibits ftsta intactin) cannt b assssd withths atfs. Fth, st c-basd scnst dtct cytstatic cyttxic actiitis a gad taidy diiding t c ins (ths that ha adbing ti f ss than th datin f th assay)and thf s sw-gwing t c ins wint b anab t scning n this atf.

Th csitin f ct dia and th snc ffta bin s in standad ct ast ctainy

fai t cisy caitat th fats f t cgwth in vivo. Siiay, th nn-hysigica xygns tyicay sd in c ct stdis ay haan itant iact n sns t agnts that tagtDNA daag athways hyxia-dndnt ath-ways. In s cass, th ang f tatina changsin ts ay b swhat distinct f that fth c ins stabishd f ths ts. This isxifid by 53 tatins, which a f-qnt in c ins cad with iay haat-itic t cs74. This tntiay fcts thfact that th ts that cay 53 tatins ayb ch sitab f in vitro stabishnt as

Box 2 | sttiiti -- ug th bi tivtig utti

The pie chart (see the figure) shows the distribution of various reported activating

oncogenic mutations in a survey of 139 non-small-cell lung cancer (NSCLC)-derived cell

lines. Also shown for all the activating mutations (except KRAS) are inhibitors that

selectively target the activated oncoproteins, yielding growth inhibition and/or

apoptosis of cancer cell lines with the corresponding mutated oncogenes. There are

currently no inhibitors that target oncogenic KRAS.

G Ocogicctitio

Fqucy rfs

Ptits Cis

EGFR Deletion(DE746-A750),

point mutation(L858R) andamplification

1040% 5% 43,48

ALK Translocation(EML4ALK)

37% 2% 49,148

MET Amplification 11% 2% 48,149

PDGFR Amplification 13% 1% 52,53

ROS Translocation(CD74ROS)

1% 2% 53

ERBB2 Insertion 24% 1% 150,151BRAF Point mutation

(exon 11)3% 6% 152,153

PIK3CA Point mutation 2% 10% 154

MEK1 Point mutation 0.50% 1% 155

EGFR, epidermal growth factor receptor; PDGFR, platelet-derivedgrowth factor.

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annt c ins. rgadss f th basis f schdiffncs, ths gnty distinctins tntiaycnstitt an itant basis f dg snsitiity dif-fncs btwn iay t cs and stabishdcanc c ins.

Additina caats assciatd with th s f cin ans as ds f th han disas incd thfact that s t tys (f xa, stat) adiffict t agat in vitro, and a thf ikyt b nd-sntd. m, th is iky tb s bias in c in sntatin sting fth ssibiity that t cs f ais disasstags and canc sbtys ay nt adat qiantyin ct. Th is as a gwing awanss angcanc sachs f c in idntity isss that cancicat th inttatin f findings. Dsit thsiitatins, th abiity t cat dg snsitiity dataf ag nbs f han canc c ins with

ais fs f gnic infatin (tatin dataf -sqncing stdis, gn xssin infa-tin f icaays and gn cy nb f sin-

g nctid yhis (SNp) aays) cnstittsa wf and fasib aach t faciitat th idnti-ficatin f signats biaks f dg snsitiitythat can tntiay b sd t idntify atints wha iky t di bnfit f a atica tagtdthatic.

3d utu yt ug vpt

Rationale. o th ast fw yas, gat awanssf th itanc f th t icninntand th th-dinsina (3D) ascts f sidts in th tignic css and th snst thay has td ffts t d ths fatsf t c gwth in vitro cisy. Tcs gwing in 3D cts a gnay bidt csy iic thi cntats in vivo7580.Thf, 3D cts ha bgn t nc asctsf t bigy and t tastass (f xa-, inasi tntia, changs in aity, atix-indndnt sia, and snsitiity t dgs andadiatin81,82). exas f 3D ct systs incd,tiay c systs, atix-bddd 3D c-ts, hw fib-basd aachs, ex vivo tcts and tica t shids (mTCS;iwd in Ref. 83). In th fwing sctins, wdscib ais 3D atfs and thi aicatin instdis aid at cidating th basis f canc dg

snsitiity and sistanc in vivo.

Hollow fibre assays.on f th tchngica inna-tins ging f th NCI60 ga was thdnt f th hw fib assay84 that was basdn is tchniqs f icncasatin andth ctiatin f aaian cs in hw fibs8587.Hw, th hw f ib assay, as it is cnty sdat th NCI, is nt a stand-an tchngy f dg dis-cy. Instad, th tc ins sht-t in vitroct (2448 hs) f a an f 12 han tc ins in bicatib hw fibs, fwd byth iantatin f ths stcts sbctansy

intaitnay in nd ic. Thf, this systxains th abiity f th adinistd dg t accsstw haacgica catnts and can b sdt assss t snss t dg tatnt in thstw catnts. Tyicay, ic a tatd with thcandidat anticanc agnt f 4 days, aft which thfibs a d and t c iabiity is anaysdby standad c iabiity assays (fiG. 1a). This sht-t assay gaty dcs th ti and ant fdg qid f standad in vivo fficacy tsting. Inadditin, it faciitats th in vivo anaysis f dg ffctsn han t c ins that d nt f tsin anias. oa, gd catin was bsdbtwn th snsitiity f dgs in th NCI60 and h-w fib assays88. Fth, dgs that shw fficacyin hw fib assays gnay shw gd anti-tactiity in han xngafts8890, and s this systis gnay sd as a -scn bf xn-si and ti-cnsing han xngaft tsting isndtakn (TABle 3).

MTCS. Th mTCS syst (fiG. 1b) is ang th stw chaactizd 3D ct systs, and is bidt accaty siat in vivo gwth f t csbth in ts f thi athhysigy and snst thay9194. Th mTCS syst has as bn sd txain ais ascts f canc thatics schas tabic and chica gadints, t hyxia,cc and catix intactins, and ch-sistanc and adisistanc95100. us f th mTCSsyst t aat dg fficacy, as a snt tnay-basd assays and bf wh-aniastdis, has bn cnsidd bt has nt yt bnintd83,101.

Limitations and perspective. 3D ct tchniqs asti in thi infancy, and dsit th any adantagsthat thy tntiay ff, it wi b s ti bfths thdgis nt th ainsta f ag-sca dg discy and dnt gas.Ths ging tchngis a cnty hadby sbstantia tchnica changs that a assciatdwith th gnatin, agatin and tsting f thsgantyic cts that sy iits thi s. Tdat, fw than 100 han t c ins habn shwn t ha th caacity t gw in shidcts94. And haf th c ins in th NCI60 and nt f mTCS83, and th hw fib assay as it is

cnty intd ss ny 12 han canc cins89. As add t ai, tsting with a sa nbf c ins iits th tntia t cat th gnichtgnity f canc, and th qint f ian-tatin in nd ic with th hw fib assay systgaty incass th cst and ti f th assay, cd-ing its s as a high-thght atf. m, th

ais 3D c ct systs a iant f cancsf th bd that cis axiaty n-thid fa han cancs.

Anth aa that qis fth instigatin is thcaisn btwn dg snss in tw-dinsina(2D) and 3D c ct systs t dtin hw thy

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|

Mechanical methods that preventattachment for example, gyratory shakers,

roller flasks and spinner flasks

Mechanical methods to promoteaggregation centrifugal compression into a cell

pellet followed by gently raisingthe pellet into culture medium

Coating tissue culture surface withnon-adhesive surfaces

for example, agarose, BD Matrigel,poly HEMA and poly lysine

Hanging drop method as for embryoid bodies

Subcutaneous implants Intraperitoneal implants

PVDF fibre

Humantumour cells

Heat-sealthe ends

Cells growing inhollow fibres

2448 h

Drug or vehicle(intraperitonealinjection)

34 d

Count cells inhollow fibresin drug-treatedcompared withvehicle-treated

mice

a

b

Enzymaticormechanicaldissociation

Single-cellsuspension

Homotypic spheroids

Heterotypic spheroids

Endothelialcells

Smoothmusclecells orosteoblasts

Seeding conditions

Tumour cells

Tumour cellsor homotypicspheroids and

endothelial cells ortumour-derivedstromal cells

34 d

Orthotopic model

Tuour gratd by th

troducto o hua tuourragt or c to th

a aatoca t a

aa a tho ro whch th

tuour aro hua.

Autochthonous model

A dogou or in situ

tuour that vov ro

ora c a aa (or

xap, chcay ducd

tuour). Th cotrat to

tuour od whch

xogou tuour c ar

patd to a aa

(xograt).

at t dg snss in vivo. Ns stdis hadcntd diffncs in canc dg snsitiity btwncs ctd in nays and ths gwn in 3D c-ts102106. pis stdis ha shwn that s dgsa ffcti in 3D c ct systs (cadwith 2D systs)107111 athgh th dgs shw gatactiity in th 2D c ct systs100,112,113, tntiayfcting diffntia gn xssin btwn th twstats114116. It is iky that ft tchngica adancs

wi c any f ths bstacs and that 3D ccts wi gaday b intgatd int high-thghtdg discy and dnt atfs (TABle 3).Hw, it is wth nting that it ains t b dfini-tiy dnstatd that dg snsitiity data didf 3D ct ds cats cinicay antsnss faithfy than standad 2D ct.

ai t vut ug iy

Th qstin f whth nt han txngafts a gd sgats f th ts fwhich thy iginat ains highy cntsia.Sa stdis ha dcntd th a sfnss

f ths systs in dicting cinica actiity117119, btths ha qstind this88,120,121. oa, athghxngafts f han canc c ins ha bn s-f f stabishing th haacgica tis fnw agnts, thy ha bn ss iab as a adtf dg fficacy. This is highightd by th disaint-ing cinica fanc f any candidat anticancagnts that shwd gat is in xngaft d-s122 (iwd in Ref. 123) (TABle 3). on f th tn-

tia isss assciatd with xngafts as ds f dgfficacy ats t inaiat dsing. Ths, cntstdis dnstatd that at cinicay ant dss,ts gwing as xngafts in ic snddsiiay t th igina ts in hans 124126.With id ania ds f han tssch as orthotopc od, tastatic ds andautochthoouod, as w as gnticay ngindcanc ds (iwd in Refs 127,128), th dict-abiity f discing cinicay sf agnts is ikyt i in th ft, and ania ds wi cn-tin t ha an itant in anticanc dgdnt. m, s xngafts ain a

Figure 1 | Thdimsio c cutu ssys. | In hollow fibre assays human tumour cells are flushed into

semi-permeable polyvinylidene fluoride (PVDF) fibres with an internal diameter of 1 mm and a 500 kDa molecular

weight exclusion. The fibres are heat sealed at 2 cm intervals and these tubular bags of cells are grown under

standard tissue culture conditions for 2448 hours. These hollow fibres with growing cells are then implanted

subcutaneously and intraperitoneally into mice. As the cells are isolated in the hollow fibres, it is possible to implant

several different human tumour cell lines simultaneously into a single mouse. Mice are then allowed to recover for

34 days and subsequently treated with either the drug or vehicle, injected intraperitoneally. After 34 days of drug

treatment, the hollow fibres are surgically removed and the surviving cells in the hollow fibres are quantified in

drug-treated mice compared with vehicle-treated mice to determine drug efficacy. b | In multicellular tumour

spheroids (MCTS) single cell suspensions of human tumour cells are seeded under conditions that prevent

attachment to plastic but promote attachment to each other (see the seeding conditions box in the figure). Byseeding tumour cells singly or by mixing them with other cells, it is possible to generate homotypic or heterotypic

spheroids, respectively.

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ita t aticay in th bitchngy andhaactica indstis f assssing th abiity f

ais inst igatina agnts t ffctiy ntatt tiss in vivo and t sss th fnctin fthi tagt.

Limitations and perspective.obis iitatins f aania ds that cd thi s in ag-sca dgdiscy gas incd thi nsitabiity fhigh-thght dg scning wing t cnsidatinsf sac, ti and cst (TABle 3). m, acss th

ais ania ds, cnt stdis ha highightditant diffncs in dg fficacy in ic with tans-antd ts cad with gnticay nginds ds f th sa t ty129 (TABle 3).

Athgh th stdis ntind ab ag in faf gnticay ngind s ds, th ts

in ths ic, which by dfinitin a agy gnti-cay hgns, fai t adqaty cat thadditina gnic htgnity that ss t b ahaak f han canc, and which snts anitant dtinant f aiab sns t tat-nt. Thf, ach f ths ds is assciatdwith itant caats, and it ains nca whichf th wi tiaty t b th st sf fdicting th cinica actiity f nw instigatinaagnts in th tatnt f han canc.

In say, ag-sca canc c in-basddg snsitiity scns a ging as an i-tant cnnt f dg discy and dnt

Table 3 | c i pt ig ti thputi

Ptfom Thoughput Dugdiscoy

Dugdopmt

Hms rfs

NCI60 High throughputfor drugs but lowthroughput for celllines

Yes Yes Discovery that drugs with similar profiles have a similar modeof action led to the development of the COMPARE algorithm

Development of clustered heat maps to showinter-relatedness of large molecular biological data sets

Discovery that broad chemotherapeutic resistancecorrelates with expression ofMDR1

Discovery of bortezomib (Velcade; MilleniumPharmaceuticals), UCN-01, flavopiridol (Alvocidib;Sanofi Aventis) and romidepsin (Istodax; GloucesterPharmaceuticals)

131139

JFCR36 High throughputfor drugs but lowthroughput for celllines

Yes Yes Using the COMPARE algorithm and advanced data miningtechniques, this platform has been successful in identifyingseveral new anticancer agents as well as biomarkers

141147

CMT1000 High throughputfor cell lines but lowthroughput for drugs

No Yes Captures the genetic heterogeneity of cancer by enlargingthe number of cancer cell lines in the panel

Discovery that cell lines with sensitivity to EGFR, ERBB2,MET, PDGFR, ALK and BRAF kinase inhibitors have activatingmutations in these genes

4753

Tissue-specificcancer cellline panels

Low throughput forboth drugs and celllines

No Yes Captures the genetic heterogeneity of a specific tumourtype by enlarging the number of cancer cell lines ofthat particular tumour type (for example, breast cancer,melanoma and non-small-cell lung cancer)

Integrates data from multiple platforms (including, copynumber, mutations, proteomic and pathway activation) toderive signatures predictive of drug sensitivity

Demonstrates that cultured tumour-derived cell lines havegenetic alterations that reflect primary tumours

45,46,5963

Hollow fibreassays


No Yes Used in conjunction with nude mice, this assay facilitates thein vivo analysis of drug effects on human tumour cell linesthat do not form tumours in animals

Overall, good correlation was observed when comparingthe sensitivity of drugs in the NCI60 screen and hollow fibreassays

8488

Xenografts Low throughput for

both drugs and celllines

No Yes Originally used by the NCI DTP for anticancer drug

screening, but abandoned for lack of predictability of drugsensitivity in solid tumours

Discovery of paclitaxel (Taxol; BristolMyers Squibb)

156

Geneticallyengineeredmouse models


No Yes Uncovered differences in drug efficacy in mice withtransplanted tumours compared with geneticallyengineered mouse models of the same tumour type

Failure to adequately capture the genetic heterogeneitythat is a hallmark of human cancer and an importantdeterminant of variable response to treatment

126129

CMT, Center for Molecular Therapeutics; DTP, Developmental Therapeutics Program; EGFR, epidermal growth factor receptor; JFCR, Japanese Foundation forCancer Research; NCI, National Cancer Institute; PDGFR, platelet-derived growth factor receptor.

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1. Shoemaker, R. H. The NCI60 human tumour cell line

anticancer drug screen. Nature Rev. Cancer6,

813823 (2006).

A comprehensive review of the NCI60 anticancer

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methodology and major achievements.

2. Sledge, G. W. Jr, Loehrer, P. J. Sr, Roth, B. J. &

Einhorn, L. H. Cisplatin as first-line therapy for

metastatic breast cancer.J. Clin. Oncol.6,

18111814 (1988).

3. Bezwoda, W. R., Seymour, L. & Ariad, S. High-dose

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Oncology49, 104107 (1992).

4. Margolin, K. A. et al. Effective initial therapy of

advanced breast cancer with fluorouracil and high-

dose, continuous infusion calcium leucovorin.J. Clin.

Oncol.10, 12781283 (1992).

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AcknowledgementsWe apologise to the authors of many relevant publications

that we were unable to cite owing to space limitations.

Competing interests statementThe authors declare no competing financial interests.

daTaBasesEntrez Gene:http://www.ncbi.nlm.nih.gov/geneBRAF

National Cancer Institute Drug Dictionary:

http://www.cancer.gov/drugdictionary

bevacizumab | cetuximab | dasatinib| erlotinib | gefitinib|

gemcitabine|imatinib|lapatinib | nilotinib | panitumumab|

sorafenib|sunitinib|trastuzumab

UniProtKB:http://www.uniprot.org

ALK| EGFR|PDGFC| PDGFRA

fUrTHer InformaTIonJeff Settlemans homepage: http://www.mgh.harvard.edu/

cancer/research/researchlab.aspx?id=1192

CancerCellLineProject:

http://www.sanger.ac.uk/genetics/CGP/CellLines

Developmental Therapeutics Program:http://dtp.nci.nih.gov/index.html

all lInkS are aCTIve In THe OnlIne PDF

R E V I E W S
http://www.ncbi.nlm.nih.gov/genehttp://www.ncbi.nlm.nih.gov/gene/673?ordinalpos=4&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.cancer.gov/drugdictionary/http://www.cancer.gov/drugdictionary/?CdrID=43234http://www.cancer.gov/drugdictionary/?CdrID=42384http://www.cancer.gov/drugdictionary/?CdrID=315885http://www.cancer.gov/drugdictionary/?CdrID=315885http://www.cancer.gov/drugdictionary/?CdrID=38428http://www.cancer.gov/drugdictionary/?CdrID=43649http://www.cancer.gov/drugdictionary/?CdrID=43649http://www.cancer.gov/drugdictionary/?CdrID=657337http://www.cancer.gov/drugdictionary/?CdrID=657337http://www.cancer.gov/drugdictionary/?CdrID=37862http://www.cancer.gov/drugdictionary/?CdrID=37862http://www.cancer.gov/drugdictionary/?CdrID=37862http://www.cancer.gov/drugdictionary/?CdrID=269659http://www.cancer.gov/drugdictionary/?CdrID=269659http://www.cancer.gov/drugdictionary/?CdrID=435988http://www.cancer.gov/drugdictionary/?CdrID=37857http://www.cancer.gov/drugdictionary/?CdrID=37857http://www.cancer.gov/drugdictionary/?CdrID=299013http://www.cancer.gov/drugdictionary/?CdrID=299013http://www.cancer.gov/drugdictionary/?CdrID=299061http://www.cancer.gov/drugdictionary/?CdrID=299061http://www.cancer.gov/drugdictionary/?CdrID=299061http://www.cancer.gov/drugdictionary/?CdrID=42265http://www.cancer.gov/drugdictionary/?CdrID=42265http://www.uniprot.org/http://www.uniprot.org/http://www.uniprot.org/uniprot/Q9UM73http://www.uniprot.org/uniprot/Q9UM73http://www.uniprot.org/uniprot/P00533http://www.uniprot.org/uniprot/P00533http://www.uniprot.org/uniprot/Q9NRA1http://www.uniprot.org/uniprot/Q9NRA1http://www.uniprot.org/uniprot/Q9NRA1http://www.uniprot.org/uniprot/P16234http://www.mgh.harvard.edu/cancer/research/researchlab.aspx?id=1192http://www.mgh.harvard.edu/cancer/research/researchlab.aspx?id=1192http://www.sanger.ac.uk/genetics/CGP/CellLines/http://www.sanger.ac.uk/genetics/CGP/CellLines/http://www.mgh.harvard.edu/cancer/research/researchlab.aspx?id=1192http://www.mgh.harvard.edu/cancer/research/researchlab.aspx?id=1192http://www.uniprot.org/uniprot/P16234http://www.uniprot.org/uniprot/Q9NRA1http://www.uniprot.org/uniprot/P00533http://www.uniprot.org/uniprot/Q9UM73http://www.uniprot.org/http://www.cancer.gov/drugdictionary/?CdrID=42265http://www.cancer.gov/drugdictionary/?CdrID=299061http://www.cancer.gov/drugdictionary/?CdrID=299013http://www.cancer.gov/drugdictionary/?CdrID=37857http://www.cancer.gov/drugdictionary/?CdrID=435988http://www.cancer.gov/drugdictionary/?CdrID=269659http://www.cancer.gov/drugdictionary/?CdrID=37862http://www.cancer.gov/drugdictionary/?CdrID=657337http://www.cancer.gov/drugdictionary/?CdrID=43649http://www.cancer.gov/drugdictionary/?CdrID=38428http://www.cancer.gov/drugdictionary/?CdrID=315885http://www.cancer.gov/drugdictionary/?CdrID=42384http://www.cancer.gov/drugdictionary/?CdrID=43234http://www.cancer.gov/drugdictionary/http://www.ncbi.nlm.nih.gov/gene/673?ordinalpos=4&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/gene

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