dc.contributor.author | Bery, N | |
dc.contributor.author | Miller, A | |
dc.contributor.author | Rabbitts, T | |
dc.date.accessioned | 2020-11-03T15:56:41Z | |
dc.date.issued | 2020-06-26 | |
dc.identifier.citation | Nature communications, 2020, 11 (1), pp. 3233 - ? | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4210 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.doi | 10.1038/s41467-020-17022-w | |
dc.description.abstract | Tumour-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.format | Electronic | |
dc.format.extent | 3233 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice, Nude | |
dc.subject | Neoplasms | |
dc.subject | Macromolecular Substances | |
dc.subject | ras Proteins | |
dc.subject | Protein Engineering | |
dc.subject | Signal Transduction | |
dc.subject | Apoptosis | |
dc.subject | Cell Proliferation | |
dc.subject | Mutation | |
dc.subject | Mutant Proteins | |
dc.subject | Proteolysis | |
dc.subject | Protein Domains | |
dc.title | A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-05-29 | |
rioxxterms.versionofrecord | 10.1038/s41467-020-17022-w | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-06-26 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature communications | |
pubs.issue | 1 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 11 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Chromosomal Translocations and Intracellular Antibody Therapeutics | |
dc.contributor.icrauthor | Rabbitts, Terence | |