Silent mutations reveal therapeutic vulnerability in RAS Q61 cancers
Abstract
RAS family members are the most frequently mutated oncogenes in human cancers. Although KRAS(G12C)-specific inhibitors show clinical activity in patients with cancer 1-3, there are no direct inhibitors of NRAS, HRAS or non-G12C KRAS variants. Here we uncover the requirement of the silent KRAS G60G mutation for cells to produce a functional KRAS(Q61K). In the absence of this G60G mutation in KRAS Q61K, a cryptic splice donor site is formed, promoting alternative splicing and premature protein termination. A G60G silent mutation eliminates the splice donor site, yielding a functional KRAS(Q61K) variant. We detected a concordance of KRAS Q61K and a G60G/A59A silent mutation in three independent pan-cancer cohorts. The region around RAS Q61 is enriched in exonic splicing enhancer (ESE) motifs and we designed mutant-specific oligonucleotides to interfere with ESE-mediated splicing, rendering the RAS(Q61) protein non-functional in a mutant-selective manner. The induction of aberrant splicing by antisense oligonucleotides demonstrated therapeutic effects in vitro and in vivo. By studying the splicing necessary for a functional KRAS(Q61K), we uncover a mutant-selective treatment strategy for RAS Q61 cancer and expose a mutant-specific vulnerability, which could potentially be exploited for therapy in other genetic contexts.
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The KRASG12D mutation has intrinsic wildtype and SOS1 guanine exchange activities, while the KRASQ61 mutation has deficiencies in GTP hydrolysis.
“The KRASG12D mutation has an intrinsic wildtype and SOS1 guanine exchange activities while the KRASQ61 mutation has deficiencies in GTP hydrolysis27,30.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [30]
The regions surrounding codon Q61 in KRAS, NRAS, and HRAS are particularly susceptible to splicing errors.
“This discovery highlighted that the regions surrounding codon Q61 in KRAS, NRAS, and HRAS are particularly susceptible to splicing errors.”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [84]
Nucleic acid therapeutics act directly on targets like mRNA.
“Unlike gene therapies, which introduce specific DNA genes into the body to induce mRNA expression and subsequent protein production, nucleic acid therapeutics act directly on targets like mRNA [84].”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [84]
Kobayashi et al. identified that silent mutations are essential for the oncogenicity of the KRAS Q61K mutation.
“Kobayashi et al. identified that silent mutations (genetic mutations that do not alter the amino acid sequence of the protein) are essential for the oncogenicity of the KRAS Q61K mutation.”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [84]
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Self-citation
- Authors
- Kobayashi, Y., Chhoeu, C., Li, J., Price, K. S., Kiedrowski, L. A., Hutchins, J. L., Hardin, A. I., Wei, Z., Hong, F., Bahcall, M., Gokhale, P. C., & Jänne, P. A.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Guardant (United States) (US)
- Corresponding author
- Kobayashi, Yoshihisa
- ORCID
- Venue
- Nature
- Published
- 2022-03-02
- Volume
- 603
- Issue
- 7900
- Pages
- 335-342
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W4214922368
- Semantic Scholar
- 2ed4d897395004e2654f7e40eb9f38ed54868855
- Cited by
- 56
- References
- 47
- Citations by year
- 2026: 5 · 2025: 17 · 2024: 15 · 2023: 9 · 2022: 10
- FWCI
- 4.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- KRAS G12C, synonymous mutations, cryptic splice donor site, alternative splicing, exonic splicing enhancers, antisense oligonucleotides, oncogenic Ras
- MeSH terms
- Silent Mutation, Humans, Neoplasms, Oncogenes, Proto-Oncogene Proteins p21(ras), Oligonucleotides, Antisense, Alternative Splicing, RNA Splice Sites
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