The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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Popow, J., Farnaby, W., Gollner, A., Kofink, C. et al. Science. 385 (6715): 1338-1347 (2024).
doi: 10.1126/science.adm8684.
Summary of the findings
Summary of the findingsMore than 40 years after the identification of RAS as bona fide oncogenes, only one allele of one isoform, the Glycine to Cysteine mutation of KRAS, has been successfully drugged to date. Here we describe a biophysics and structure guided approach towards the discovery of ACBI3, a small molecule that can potently degrade wildtype KRAS as well as 13 out of the 17 most prevalent oncogenic KRAS alleles, including the most prevalent alleles, G12D and G12V. We demonstrate both rapid and potent cellular degradation is coupled with more profound and sustained pathway modulation as compared with inhibition. We support a detailed understanding of how a series of prototype bifunctional degraders induce de novo ternary complexes between KRAS and the E3 ligase recognition sub-unit von Hippel-Lindau protein (VHL) with both high-resolution X-ray co-crystal and cryo-EM ternary structures, which guided our compound optimisation. Subsequently, we demonstrate that degradation of oncogenic KRAS leads to tumour regression in vivo in both G12D and G12V models.
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Future impact
These findings support that a single targeted protein degrader molecule may be capable of addressing a major proportion of KRAS driven cancers.
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