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PreprintCited by 8Protein Kinase Regulation and GTPase SignalingProtein Tyrosine PhosphatasesMelanoma and MAPK Pathways

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Illuminating oncogenic KRAS signaling by multi-dimensional chemical proteomics

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Kabella, Nicole, Bayer, Florian P., Stamatiou, Konstantinos, Abele, Miriam, Sakhteman, Amirhossein, Chang, Yun-Chien, Wagner, Vinona, Gabriel, Antje, Krumm, Johannes, Reinecke, Maria, Holzner, Melanie, Aigner, Michael, The, Matthew, Hahne, Hannes, Bassermann, Florian, Ludwig, Christina, Vagnarelli, Paola, Kuster, Bernhard·2025·Science Signaling
DOI 10.1101/2025.01.30.635627

Preprint — published as 10.1126/scisignal.adt6552 · Paper page

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Abstract

Mutated KRAS is among the most frequent activating genetic alterations in cancer and drug discovery efforts have led to inhibitors that block its activity. To better understand oncogenic KRAS signaling and the cytostatic effects of drugs, we performed comprehensive dose-dependent proteome-wide target deconvolution, pathway engagement and protein expression characterization of KRAS, MEK, ERK, SHP2 and SOS1 inhibitors in pancreatic (KRAS G12C, G12D) and lung cancer (KRAS G12C) cells. Analysis of the resulting 687,954 dose-response curves available online revealed both common and cell line-specific signaling networks dominated by oncogenic KRAS activity. Time-dose experiments separated early KRAS-MEK-ERK from CDK-mediated signaling that cause cells to exit from the cell cycle. This transition to a quiescent state occurred without substantial proteome re-modelling but extensive changes of protein phosphorylation and ubiquitylation. The collective data highlights the complexity of KRAS signaling in cancer and places a large number of new proteins into this functional context.

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Metadata

Authors
Kabella, N., Bayer, F. P., Stamatiou, K., Abele, M., Sakhteman, A., Chang, Y.-C., Wagner, V., Gabriel, A., Krumm, J., Reinecke, M., Holzner, M., Aigner, M., The, M., Hahne, H., Bassermann, F., Ludwig, C., Vagnarelli, P., & Kuster, B.
Affiliations
  • Technical University of Munich (DE)
  • Brunel University of London (GB)
  • TUM Klinikum (DE)
ORCID
Venue
Science Signaling
Publisher
openRxiv
Published
2025-02-01
Volume
18
Issue
897
Pages
eadt6552-eadt6552
ISSN
1937-9145 (ISSN-L)
DOI
10.1101/2025.01.30.635627
OpenAlex
W4412721444
Cited by
8
References
1
Citations by year
2026: 6 · 2025: 2
FWCI
2.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Science Signaling (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed (publishedVersion)
  • Brunel University Research Archive (BURA) (Brunel University London) (publishedVersion)
  • Brunel University Research Archive (BURA) (Brunel University London) (submittedVersion, cc-by-nc-nd)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
Funders
  • Wellcome Trust (210742/Z/18/Z)
  • European Commission (833710, HORIZON2020)
  • Deutsche Forschungsgemeinschaft (SFB 1309, SFB1321)
  • Bundesministerium für Bildung und Forschung (031L0305A)
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 › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords
KRAS G12C, KRAS G12D, KRAS inhibitors, MEK/ERK signaling, SHP2, SOS1, phosphoproteome, ubiquitination, cell cycle exit, drug resistance, pancreatic cancer, lung cancer, post-translational modification
MeSH terms
Humans, Lung Neoplasms, Mutation, Pancreatic Neoplasms, Signal Transduction, Proto-Oncogene Proteins p21(ras), Proteome, SOS1 Protein, MAP Kinase Signaling System, Proteomics, Cell Line, Tumor, Protein Tyrosine Phosphatase, Non-Receptor Type 11

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