Evidence map›Paper›PMID 40517320›Full record

ArticleMolecular oncology2025

A nucleotide-independent, pan-RAS-targeted DARPin elicits anti-tumor activity in a multimodal manner.

Jonas N Kapp, Wouter P R Verdurmen, Jonas V Schaefer, Kari Kopra, Gabriela Nagy-Davidescu, Elodie Richard, Marie-Julie Nokin, Patrick Ernst, Rastislav Tamaskovic, Martin Schwill and 4 more

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Article in Molecular oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Protein engineering: status report.Protein engineering, design & selection : PEDS · 2026
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Jonas N KappDepartment of Biochemistry, University of Zurich, Switzerland.
Wouter P R VerdurmenDepartment of Biochemistry, University of Zurich, Switzerland.
Jonas V SchaeferDepartment of Biochemistry, University of Zurich, Switzerland.
Kari KopraDepartment of Chemistry, University of Turku, Finland.ORCID 0000-0001-7585-6020
Gabriela Nagy-DavidescuDepartment of Biochemistry, University of Zurich, Switzerland.
Elodie RichardBordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, France.
Marie-Julie NokinLaboratory of Biology of Tumor and Development (LBTD), GIGA-Cancer, University of Liege, Belgium.
Patrick ErnstDepartment of Biochemistry, University of Zurich, Switzerland.
Rastislav TamaskovicDepartment of Biochemistry, University of Zurich, Switzerland.
Martin SchwillDepartment of Biochemistry, University of Zurich, Switzerland.
Ralph DegenDepartment of Biochemistry, University of Zurich, Switzerland.
Claudia SchollDivision of Applied Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
David SantamariaACTION Laboratory, IECB, INSERM U1218, University of Bordeaux, France.
Andreas PlückthunDepartment of Biochemistry, University of Zurich, Switzerland.ORCID 0000-0003-4191-5306

Funding

Research Council of Finland 296225Research Council of Finland 323433Research Council of Finland 329012Research Council of Finland 53324Swiss Cancer Research Foundation KFS 4147-02-2017Swiss Cancer Research Foundation KFS-5290-02-2021-R
6 · The paper itself

Abstract

The KRAS oncoprotein is a frequent tumor driver in lung, pancreatic, and colorectal cancers and has proven to be a challenging pharmaceutical target. The first KRAS-targeted therapeutics are now being tested in clinical trials but the consequences of preferentially targeting the GDP or GTP state of KRAS and the relevance of RAS nanoclustering have remained unclear. Here we report a Designed Ankyrin Repeat Protein (DARPin) that recognizes the RAS switch I/II region with low nm affinity, independently of the nucleotide bound (GDP- or GTP state). This DARPin, termed '784_F5', occupies the effector recognition lobe, resulting in interference with SOS-mediated activation, RAS downstream effector interactions, and KRAS nanoclustering. Consequently, this anti-RAS DARPin potently blocks downstream signaling, leading to a strong reduction in proliferation and anchorage-independent growth in RAS-dependent cell lines. We showed that the expression of '784_F5', the pan-RAS, nucleotide-independent DARPin can lead to tumor regression in a colorectal xenograft model which may hold promise for further investigation and development.

Indexed as

Ankyrin RepeatAntineoplastic AgentsProto-Oncogene Proteins p21(ras)ras ProteinsAnimalsCell Line, TumorCell ProliferationColorectal NeoplasmsHumansMiceNucleotidesSignal TransductionXenograft Model Antitumor AssaysAntineoplastic AgentsKRAS protein, humanNucleotidesProto-Oncogene Proteins p21(ras)ras ProteinscancerDesigned Ankyrin Repeat Proteindrug developmentoncogeneRASsmall GTPase

Identifiers

PMID40517320
PMCPMC12591329

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.