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dc.contributor.authorMartins, CD
dc.contributor.authorDa Pieve, C
dc.contributor.authorBurley, TA
dc.contributor.authorSmith, R
dc.contributor.authorCiobota, DM
dc.contributor.authorAllott, L
dc.contributor.authorHarrington, KJ
dc.contributor.authorOyen, WJG
dc.contributor.authorSmith, G
dc.contributor.authorKramer-Marek, G
dc.date.accessioned2018-04-20T09:34:53Z
dc.date.issued2018-04
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2018, 24 (8), pp. 1853 - 1865
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1649
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-17-2754
dc.description.abstractPurpose: Recent studies have highlighted a role of HER3 in HER2-driven cancers (e.g., breast cancer), implicating the upregulation of the receptor in resistance to HER-targeted therapies and Hsp90 inhibitors (e.g., AUY922). Therefore, we have developed an affibody-based PET radioconjugate that quantitatively assesses HER3 changes induced by Hsp90 inhibition in vivoExperimental Design: ZHER3:8698 affibody molecules were conjugated via the C-terminus cysteine to DFO-maleimide for 89Zr radiolabeling. The probe was characterized in vitro and in vivo in a panel of human breast cell lines and xenograft models with varying HER3 receptor levels. In addition, the radioconjugate was investigated as a tool to monitor the outcome of AUY922, an Hsp90 inhibitor, in an MCF-7 xenograft model.Results: We demonstrated that 89Zr-DFO-ZHER3:8698 can track changes in receptor expression in HER3-positive xenograft models and monitor the outcome of AUY922 treatment. Our in vitro findings showed that MCF-7 cells, which are phenotypically different from BT474, develop resistance to treatment with AUY922 through HER3/IGF-1Rβ-mediated signaling. Of note, the lack of response in vitro due to HER3 recovery was confirmed in vivo using 89Zr-DFO-ZHER3:8698-based imaging. Upon AUY922 treatment, higher radioconjugate uptake was detected in treated MCF-7 xenografts, correlating with an AUY922-induced HER3 upregulation concomitant with an increase in IGF-1Rβ expression.Conclusions: These data underline the potential of HER3-based PET imaging to noninvasively provide information about HER3 expression and to identify patients not responding to targeted therapies due to HER3 recovery. Clin Cancer Res; 24(8); 1853-65. ©2018 AACR.
dc.formatPrint-Electronic
dc.format.extent1853 - 1865
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.subjectDisease Models, Animal
dc.subjectResorcinols
dc.subjectIsoxazoles
dc.subjectReceptor, erbB-3
dc.subjectImmunoconjugates
dc.subjectRadiopharmaceuticals
dc.subjectPositron-Emission Tomography
dc.subjectRadiography
dc.subjectGene Expression Profiling
dc.subjectDrug Resistance, Neoplasm
dc.subjectFemale
dc.subjectHSP90 Heat-Shock Proteins
dc.subjectHeterografts
dc.subjectBiomarkers, Tumor
dc.titleHER3-Mediated Resistance to Hsp90 Inhibition Detected in Breast Cancer Xenografts by Affibody-Based PET Imaging.
dc.typeJournal Article
dcterms.dateAccepted2018-02-01
rioxxterms.versionofrecord10.1158/1078-0432.ccr-17-2754
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-04
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Research
pubs.issue8
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/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Preclinical Molecular Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/PET Radiochemistry
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Preclinical Molecular Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Molecular Imaging
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/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Preclinical Molecular Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/PET Radiochemistry
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Preclinical Molecular Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Molecular Imaging
pubs.publication-statusPublished
pubs.volume24
pubs.embargo.termsNot known
icr.researchteamPET Radiochemistryen_US
icr.researchteamPreclinical Molecular Imagingen_US
icr.researchteamTargeted Therapyen_US
icr.researchteamTranslational Molecular Imagingen_US
dc.contributor.icrauthorKramer-Marek, Gabrielaen
dc.contributor.icrauthorOyen, Willemen
dc.contributor.icrauthorHarrington, Kevinen
dc.contributor.icrauthorSmith, Grahamen


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