Drugging the Undruggable: Advances on RAS Targeting in Cancer
Miriam Molina-Arcas1, Amit Samani1,2, Julian Downward1,3
1Oncogene Biology Laboratory, Francis Crick Institute, London NW1 1AT, UK.
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.
Insights
Targeting KRAS mutations in cancer has been challenging. New KRAS-G12C inhibitors show promise, with combination therapies aiming to overcome resistance and improve patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Activating mutations in RAS isoforms are present in approximately 20% of all malignancies.
- Targeting RAS has been historically difficult due to its high affinity for GTP and lack of suitable binding pockets for small molecules.
- Recent advances in understanding KRAS-G12C biochemistry have led to the development of mutant-specific inhibitors.
Purpose of the Study:
- To review historical and current strategies for targeting RAS and its effector signaling pathways.
- To evaluate the efficacy of KRAS-G12C inhibitors as monotherapy and in combination regimens.
- To explore novel approaches for targeting other RAS mutant isoforms.
Main Methods:
- Review of pre-clinical and clinical evidence for KRAS-G12C inhibitor efficacy.
- Analysis of combination therapies designed to overcome resistance and enhance response durability.
- Discussion of emerging strategies for targeting non-G12C RAS mutations.
Main Results:
- KRAS-G12C specific inhibitors have been developed, with sotorasib being the first FDA-approved agent.
- Seven KRAS-G12C inhibitors are currently in clinical trials.
- Combination therapies are being investigated to address primary resistance and prolong treatment response.
Conclusions:
- Targeting KRAS-G12C represents a significant breakthrough in oncology drug development.
- Combination strategies hold potential for overcoming therapeutic limitations and improving outcomes for patients with KRAS-mutated cancers.
- Further research into novel approaches is needed to address the broader spectrum of RAS-driven malignancies.
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