Exploiting the intrinsic misfolding propensity of the KRAS oncoprotein
Open accessAbstract
Mutant KRAS is a major driver of oncogenesis in a multitude of cancers but remains a challenging target for classical small molecule drugs, motivating the exploration of alternative approaches. Here, we show that aggregation-prone regions (APRs) in the primary sequence of the oncoprotein constitute intrinsic vulnerabilities that can be exploited to misfold KRAS into protein aggregates. Conveniently, this propensity that is present in wild-type KRAS is increased in the common oncogenic mutations at positions 12 and 13. We show that synthetic peptides (Pept-ins™) derived from two distinct KRAS APRs could induce the misfolding and subsequent loss of function of oncogenic KRAS, both of recombinantly produced protein in solution, during cell-free translation and in cancer cells. The Pept-ins exerted antiproliferative activity against a range of mutant KRAS cell lines and abrogated tumor growth in a syngeneic lung adenocarcinoma mouse model driven by mutant KRAS G12V. These findings provide proof-of-concept that the intrinsic misfolding propensity of the KRAS oncoprotein can be exploited to cause its functional inactivation.
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Oncogenic mutations at positions 12 and 13, especially the G12V mutation, enhance KRAS's natural tendency towards aggregation.
“Oncogenic mutations at positions 12 and 13, especially the G12V mutation, enhance KRAS’s natural tendency towards aggregation.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [77]
Pept-ins engineered to interact with these aggregation-prone regions have been shown to induce the misfolding and aggregation of KRAS, undermining its oncogenic function.
“Pept-ins engineered to interact with these aggregation-prone regions have been shown to induce the misfolding and aggregation of KRAS, undermining its oncogenic function.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [77]
Pept-ins have been assessed both in vivo and in vitro, demonstrating that they can interrupt critical signaling pathways, prompt apoptosis, and suppress tumor proliferation.
“Pept-ins have been assessed both in vivo and in vitro, demonstrating that they can interrupt critical signaling pathways, prompt apoptosis, and suppress tumor proliferation.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [77]
Synthetic amyloidogenic peptides, termed Pept-ins, induce the misfolding and aggregation of mutant KRAS.
“Synthetic amyloidogenic peptides, termed Pept-ins, represent a novel approach developed to induce the misfolding and aggregation of mutant KRAS, moving beyond the reliance on conventional binding pockets [77].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [77]
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He, W., Xu, X., Li, H., Zhou, J., & Gao, X. (2025) · Protein Science · doi:10.1002/pro.70031 · Cited by 6 · see citing works
Heterobifunctional proteomimetic polymers for targeted degradation of MYC and KRAS
Wang, M. M., Truica, M. I., Gattis, B. S., Oktawiec, J., Sagar, V., Basu, A. A., Bertin, P. A., Zhang, X., Abdulkadir, S. A., & Gianneschi, N. C. (2026) · Nature Communications · doi:10.1038/s41467-026-68913-3 · Cited by 5 · see citing works
Louros, N. N., Rousseau, F., & Schymkowitz, J. W. H. (2024) · Bioinformatics · doi:10.1093/bioinformatics/btae279 · Cited by 5 · see citing works
Self-citationHeterobifunctional proteomimetic polymers for targeted protein degradationPreprint
Wang, M. M., Truica, M. I., Gattis, B. S., Oktawiec, J., Sagar, V., Basu, A. A., Bertin, P. A., Zhang, X., Abdulkadir, S. A., & Gianneschi, N. C. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.07.641543
Understanding aggregation of proteins in aqueous solutions and methods to study them
Rashid, M. I., Ansari, N. K., Naeem, A., & Rizvi, A. (2026) · Journal of Molecular Liquids · doi:10.1016/j.molliq.2026.129625
- Authors
- Janssen, K., Claes, F., Van de Velde, D., Wehbi, V. L., Houben, B., Lampi, Y., Nys, M., Khodaparast, L., Khodaparast, L., Louros, N., van der Kant, R., Verniers, J., Garcia, T., Ramakers, M., Konstantoulea, K., Maragkou, K., Duran-Romaña, R., Musteanu, M., Barbacid, M., Scorneaux, B., Beirnaert, E., Schymkowitz, J., & Rousseau, F.
- Affiliations
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Aelin Therapeutics, 3001 Leuven, Belgium
- Switch Laboratory, VIB-KU Leuven Center for Brain and Disease Research, 3000 Leuven, Belgium
- Universidad Complutense de Madrid (ES)
- Instituto de Salud Carlos III (ES)
- Corresponding author
- Schymkowitz, Joost
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2023-02-22
- Volume
- 120
- Issue
- 9
- Pages
- e2214921120-e2214921120
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC9992772
- OpenAlex
- W4321487980
- Cited by
- 10
- References
- 70
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 1
- FWCI
- 0.89
- 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)
- Lirias (submittedVersion, cc-by-nc-nd)
- Funders
- Stichting Tegen Kanker (FAF-F/201//1174)
- Vlaams Instituut voor Biotechnologie (C0401)
- Fonds Wetenschappelijk Onderzoek (G045920N)
- Agentschap Innoveren en Ondernemen (HBC.2018.0407, HBC.2020.2112)
- 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 › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- KRAS, protein misfolding, aggregation-prone regions, KRAS G12V, KRAS mutation, synthetic peptides, protein aggregation, loss of function, antiproliferative activity, lung adenocarcinoma, KRAS-targeted therapy, in vitro translation
- MeSH terms
- Animals, Lung Neoplasms, Mutation, Organoplatinum Compounds, Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Protein Folding, Cell Line, Tumor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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