A1 Refereed original research article in a scientific journal
A nucleotide‐independent, pan‐RAS‐targeted DARPin elicits anti‐tumor activity in a multimodal manner
Authors: Kapp, Jonas N.; Verdurmen, Wouter P. R.; Schaefer, Jonas V.; Kopra, Kari; Nagy‐Davidescu, Gabriela; Richard, Elodie; Nokin, Marie‐Julie; Ernst, Patrick; Tamaskovic, Rastislav; Schwill, Martin; Degen, Ralph; Scholl, Claudia; Santamaria, David; Plückthun, Andreas
Publisher: Wiley
Publication year: 2025
Journal: Molecular Oncology
Journal name in source: Molecular Oncology
ISSN: 1574-7891
eISSN: 1878-0261
DOI: https://doi.org/10.1002/1878-0261.70061
Web address : https://doi.org/10.1002/1878-0261.70061
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/499478243
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.
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Funding information in the publication:
This research was funded by Swiss Cancer Research foundation, grant number KFS 4147-02-2017 and KFS-5290-02-2021-R to AP and the Research Council of Finland (296225/KK, 323433/KK, 329012/KK, and 353324/KK). We thank Susanne Müller-Knapp from the Structural Genomics Consortium (SGC) in Oxford for providing the KRAS protein for the selection. We further wish to express our appreciation to Dr William Gillette and his team in the RAS Initiative at the Frederick National Laboratory, Frederick MD USA for providing the SOScat and RAF1-RBD proteins. The authors would like to thank Marie Groth for training and scientific discussion. The Figs 2A,B and 5A were created with BioRender.com.
