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dc.contributor.authorBery, N
dc.contributor.authorMiller, A
dc.contributor.authorRabbitts, T
dc.date.accessioned2020-11-03T15:56:41Z
dc.date.issued2020-06-26
dc.identifier.citationNature communications, 2020, 11 (1), pp. 3233 - ?
dc.identifier.issn2041-1723
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4210
dc.identifier.eissn2041-1723
dc.identifier.doi10.1038/s41467-020-17022-w
dc.description.abstractTumour-associated KRAS mutations are the most prevalent in the three RAS-family isoforms and involve many different amino-acids. Therefore, molecules able to interfere with mutant KRAS protein are potentially important for wide-ranging tumour therapy. We describe the engineering of two RAS degraders based on protein macromolecules (macrodrugs) fused to specific E3 ligases. A KRAS-specific DARPin fused to the VHL E3 ligase is compared to a pan-RAS intracellular single domain antibody (iDAb) fused to the UBOX domain of the CHIP E3 ligase. We demonstrate that while the KRAS-specific DARPin degrader induces specific proteolysis of both mutant and wild type KRAS, it only inhibits proliferation of cancer cells expressing mutant KRAS in vitro and in vivo. Pan-RAS protein degradation, however, affects proliferation irrespective of the RAS mutation. These data show that specific KRAS degradation is an important therapeutic strategy to affect tumours expressing any of the range of KRAS mutations.
dc.formatElectronic
dc.format.extent3233 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice, Nude
dc.subjectNeoplasms
dc.subjectMacromolecular Substances
dc.subjectras Proteins
dc.subjectProtein Engineering
dc.subjectSignal Transduction
dc.subjectApoptosis
dc.subjectCell Proliferation
dc.subjectMutation
dc.subjectMutant Proteins
dc.subjectProteolysis
dc.subjectProtein Domains
dc.titleA potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS.
dc.typeJournal Article
dcterms.dateAccepted2020-05-29
rioxxterms.versionofrecord10.1038/s41467-020-17022-w
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-06-26
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfNature communications
pubs.issue1
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 Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Chromosomal Translocations and Intracellular Antibody Therapeutics
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 Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Chromosomal Translocations and Intracellular Antibody Therapeutics
pubs.publication-statusPublished
pubs.volume11
pubs.embargo.termsNot known
icr.researchteamChromosomal Translocations and Intracellular Antibody Therapeuticsen_US
dc.contributor.icrauthorRabbitts, Terenceen


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