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dc.contributor.authorBajrami, I
dc.contributor.authorMarlow, R
dc.contributor.authorvan de Ven, M
dc.contributor.authorBrough, R
dc.contributor.authorPemberton, HN
dc.contributor.authorFrankum, J
dc.contributor.authorSong, F
dc.contributor.authorRafiq, R
dc.contributor.authorKonde, A
dc.contributor.authorKrastev, DB
dc.contributor.authorMenon, M
dc.contributor.authorCampbell, J
dc.contributor.authorGulati, A
dc.contributor.authorKumar, R
dc.contributor.authorPettitt, SJ
dc.contributor.authorGurden, MD
dc.contributor.authorCardenosa, ML
dc.contributor.authorChong, I
dc.contributor.authorGazinska, P
dc.contributor.authorWallberg, F
dc.contributor.authorSawyer, EJ
dc.contributor.authorMartin, L-A
dc.contributor.authorDowsett, M
dc.contributor.authorLinardopoulos, S
dc.contributor.authorNatrajan, R
dc.contributor.authorRyan, CJ
dc.contributor.authorDerksen, PWB
dc.contributor.authorJonkers, J
dc.contributor.authorTutt, ANJ
dc.contributor.authorAshworth, A
dc.contributor.authorLord, CJ
dc.date.accessioned2018-01-24T15:56:10Z
dc.date.issued2018-04
dc.identifier.citationCancer discovery, 2018, 8 (4), pp. 498 - 515
dc.identifier.issn2159-8274
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1026
dc.identifier.eissn2159-8290
dc.identifier.doi10.1158/2159-8290.cd-17-0603
dc.description.abstractThe cell adhesion glycoprotein E-cadherin (CDH1) is commonly inactivated in breast tumors. Precision medicine approaches that exploit this characteristic are not available. Using perturbation screens in breast tumor cells with CRISPR/Cas9-engineered CDH1 mutations, we identified synthetic lethality between E-cadherin deficiency and inhibition of the tyrosine kinase ROS1. Data from large-scale genetic screens in molecularly diverse breast tumor cell lines established that the E-cadherin/ROS1 synthetic lethality was not only robust in the face of considerable molecular heterogeneity but was also elicited with clinical ROS1 inhibitors, including foretinib and crizotinib. ROS1 inhibitors induced mitotic abnormalities and multinucleation in E-cadherin-defective cells, phenotypes associated with a defect in cytokinesis and aberrant p120 catenin phosphorylation and localization. In vivo , ROS1 inhibitors produced profound antitumor effects in multiple models of E-cadherin-defective breast cancer. These data therefore provide the preclinical rationale for assessing ROS1 inhibitors, such as the licensed drug crizotinib, in appropriately stratified patients. Significance: E-cadherin defects are common in breast cancer but are currently not targeted with a precision medicine approach. Our preclinical data indicate that licensed ROS1 inhibitors, including crizotinib, should be repurposed to target E-cadherin-defective breast cancers, thus providing the rationale for the assessment of these agents in molecularly stratified phase II clinical trials. Cancer Discov; 8(4); 498-515. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 371 .
dc.formatPrint
dc.format.extent498 - 515
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectBreast Neoplasms
dc.subjectAnilides
dc.subjectQuinolines
dc.subjectCadherins
dc.subjectProto-Oncogene Proteins
dc.subjectAntineoplastic Agents
dc.subjectAntigens, CD
dc.subjectProtein Kinase Inhibitors
dc.subjectMutation
dc.subjectFemale
dc.subjectProtein-Tyrosine Kinases
dc.subjectCrizotinib
dc.titleE-Cadherin/ROS1 Inhibitor Synthetic Lethality in Breast Cancer.
dc.typeJournal Article
dcterms.dateAccepted2018-01-23
rioxxterms.versionofrecord10.1158/2159-8290.cd-17-0603
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-04
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer discovery
pubs.issue4
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Drug Target Discovery
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Ashworth Collaborators
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Drug Target Discovery
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Ashworth Collaborators
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.publication-statusPublished
pubs.volume8
pubs.embargo.termsNot known
icr.researchteamDrug Target Discoveryen_US
icr.researchteamAshworth Collaboratorsen_US
icr.researchteamEndocrinologyen_US
icr.researchteamFunctional Genomicsen_US
icr.researchteamGene Functionen_US
dc.contributor.icrauthorSong, Feifeien
dc.contributor.icrauthorKonde, Ashaen
dc.contributor.icrauthorLinardopoulos, Spyridonen
dc.contributor.icrauthorLord, Christopheren
dc.contributor.icrauthorKrastev, Dragomiren
dc.contributor.icrauthorPettitt, Stephenen
dc.contributor.icrauthorChong, Yu-Shingen
dc.contributor.icrauthorMartin, Lesley-Annen
dc.contributor.icrauthorDowsett, Mitchen
dc.contributor.icrauthorNatrajan, Rachaelen
dc.contributor.icrauthorTutt, Andrewen
dc.contributor.icrauthorCampbell, Jamesen


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