A saturation mutagenesis screen uncovers resistant and sensitizing secondary KRAS mutations to clinical KRAS G12C inhibitors
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Significance: KRAS G12C inhibitors have demonstrated promising efficacy in non–small-cell lung cancer patients harboring the KRAS G12C mutation. However, the mechanism of resistance remains to be fully understood. To understand the consequences of single amino acid changes within KRAS G12C , we conducted a saturation mutagenesis screen of the KRAS G12C protein and assessed the mutational impact on drug sensitivity. Not only did our screen reveal resistant hits that were identified from patients’ samples (V8L, C12F, R68S, H95D, H95R, and Y96C), but we also discovered variants that sensitize the inhibition. Furthermore, we examined the human genetics databases and identified germline or somatic KRAS mutations that appear among the strong resistance hits. Our study positions future drug discovery targeting KRAS G12C toward focusing on inhibitors preserving potency against resistance mutations at key residues.
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Customised site saturation variant libraries are now favoured by many experienced MAVE laboratories.
“Such libraries are now favoured by many experienced MAVE laboratories (53); however, limited target length and cost considerations still impede global adoption in the field (52).”
From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [53]
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Massively parallel functional genomic assays in endocrinology: from promise to delivery
Xu, J., Aslanzadeh, V., Kudla, G., & Semple, R. K. (2026) · Journal of Molecular Endocrinology · doi:10.1530/jme-25-0134
- Authors
- Feng, S., Callow, M. G., Fortin, J.-P., Khan, Z., Bray, D., Costa, M., Shi, Z., Wang, W., & Evangelista, M.
- Affiliations
- Genentech (US)
- Foundation Medicine (United States) (US)
- Corresponding author
- Feng, Siyu
- Evangelista, Marie
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2022-04-26
- Volume
- 119
- Issue
- 18
- Pages
- e2120512119-e2120512119
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC9170150
- OpenAlex
- W4224987182
- Cited by
- 27
- References
- 8
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 3
- FWCI
- 3.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- KRAS G12C, KRAS inhibitors, drug resistance mutations, sotorasib, adagrasib, PI3K/AKT/mTOR pathway, non-small cell lung cancer, acquired resistance, germline mutations
- MeSH terms
- Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Piperazines, Pyridines, Pyrimidines, Proto-Oncogene Proteins p21(ras), Mutagenesis
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