Targeting mutant KRAS
Daniel A Erlanson1, Kevin R Webster1
1Frontier Medicines Corporation, 151 Oyster Point Blvd., 2nd Floor, South San Francisco, CA, 94080, USA.
Abstract:
The protein KRAS has for decades been considered a holy grail of cancer drug discovery. For most of that time, it has also been considered undruggable. Since 2018, five compounds have entered the clinic targeting a single mutant form of KRAS, G12C. Here, we review each of these compounds along with additional approaches to targeting this and other mutants. Remaining challenges include expanding the identification of inhibitors to a broader range of known mutants and to conformations of the protein more likely to avoid development of resistance.
Insights
Targeting KRAS G12C mutations in cancer has yielded five clinical compounds since 2018. Further research aims to develop inhibitors for broader KRAS mutations and prevent drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The KRAS protein is a key target in cancer drug discovery, historically considered undruggable.
- Specific KRAS mutations, like G12C, are implicated in various cancers.
Purpose of the Study:
- To review existing and emerging therapeutic strategies targeting KRAS mutations.
- To identify challenges and future directions in KRAS-targeted cancer therapy.
Main Methods:
- Review of clinical compounds targeting KRAS G12C.
- Analysis of additional approaches for targeting other KRAS mutants.
- Discussion of resistance mechanisms and inhibitor development.
Main Results:
- Five compounds targeting KRAS G12C have been approved for clinical use since 2018.
- Various other strategies are being explored for different KRAS mutations.
Conclusions:
- Targeting KRAS G12C represents a significant advancement in cancer therapy.
- Future efforts must focus on developing inhibitors for a wider range of KRAS mutations and overcoming resistance.
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