Home > Publications database > A nucleotide-independent, pan-RAS-targeted DARPin elicits anti-tumor activity in a multimodal manner. > print

001     302049
005     20250821120527.0
024 7 _ |2 pmid
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024 7 _ |2 ISSN
|a 1878-0261
024 7 _ |2 doi
|a 10.1002/1878-0261.70061
037 _ _ |a DKFZ-2025-01240
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Kapp, Jonas N
|b 0
245 _ _ |a A nucleotide-independent, pan-RAS-targeted DARPin elicits anti-tumor activity in a multimodal manner.
260 _ _ |a Hoboken, NJ
|b John Wiley & Sons, Inc.
|c 2025
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520 _ _ |a 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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650 _ 7 |2 Other
|a Designed Ankyrin Repeat Protein
650 _ 7 |2 Other
|a RAS
650 _ 7 |2 Other
|a cancer
650 _ 7 |2 Other
|a drug development
650 _ 7 |2 Other
|a oncogene
650 _ 7 |2 Other
|a small GTPase
700 1 _ |a Verdurmen, Wouter P R
|b 1
700 1 _ |a Schaefer, Jonas V
|b 2
700 1 _ |0 0000-0001-7585-6020
|a Kopra, Kari
|b 3
700 1 _ |a Nagy-Davidescu, Gabriela
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700 1 _ |a Richard, Elodie
|b 5
700 1 _ |a Nokin, Marie-Julie
|b 6
700 1 _ |a Ernst, Patrick
|b 7
700 1 _ |a Tamaskovic, Rastislav
|b 8
700 1 _ |a Schwill, Martin
|b 9
700 1 _ |a Degen, Ralph
|b 10
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|a Scholl, Claudia
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700 1 _ |a Santamaria, David
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700 1 _ |0 0000-0003-4191-5306
|a Plückthun, Andreas
|b 13
773 _ _ |0 PERI:(DE-600)2322586-5
|a DOI:10.1002/1878-0261.70061
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|t Molecular oncology
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|x 1574-7891
|y 2025
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