Drugging the Undruggable: Advances on RAS Targeting in Cancer.
Loading...
Embargo End Date
ICR Authors
Authors
Molina-Arcas, M
Samani, A
Downward, J
Samani, A
Downward, J
Document Type
Journal Article
Date
2021-06-10
Date Accepted
2021-06-04
Abstract
Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high-affinity small-molecule binding, precluded effective therapies despite decades of research. Recently, characterisation of the biochemical properties of KRAS-G12C along with discovery of its 'switch-II pocket' have allowed development of effective mutant-specific inhibitors. Currently seven KRAS-G12C inhibitors are in clinical trials and sotorasib has become the first one to be granted FDA approval. Here, we discuss historical efforts to target RAS directly and approaches to target RAS effector signalling, including combinations that overcome limitations of single-agent targeting. We also review pre-clinical and clinical evidence for the efficacy of KRAS-G12C inhibitor monotherapy followed by an illustration of combination therapies designed to overcome primary resistance and extend durability of response. Finally, we briefly discuss novel approaches to targeting non-G12C mutant isoforms.
Citation
Genes, 2021, 12 (6), pp. 899 -
Source Title
Genes
Publisher
MDPI
ISSN
2073-4425
eISSN
2073-4425
2073-4425
2073-4425
Collections
Research Team
Trans Immunotherapy
Lung Cancer Group
Lung Cancer Group