A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS.
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Date
2020-06-26ICR Author
Author
Bery, N
Miller, A
Rabbitts, T
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cell Line, Tumor
Animals
Humans
Mice, Nude
Neoplasms
Macromolecular Substances
ras Proteins
Protein Engineering
Signal Transduction
Apoptosis
Cell Proliferation
Mutation
Mutant Proteins
Proteolysis
Protein Domains
Research team
Chromosomal Translocations and Intracellular Antibody Therapeutics
Language
eng
Date accepted
2020-05-29
License start date
2020-06-26
Citation
Nature communications, 2020, 11 (1), pp. 3233 - ?
Publisher
NATURE PUBLISHING GROUP