TY  - JOUR
AU  - Kapp, Jonas N
AU  - Verdurmen, Wouter P R
AU  - Schaefer, Jonas V
AU  - Kopra, Kari
AU  - Nagy-Davidescu, Gabriela
AU  - Richard, Elodie
AU  - Nokin, Marie-Julie
AU  - Ernst, Patrick
AU  - Tamaskovic, Rastislav
AU  - Schwill, Martin
AU  - Degen, Ralph
AU  - Scholl, Claudia
AU  - Santamaria, David
AU  - Plückthun, Andreas
TI  - A nucleotide-independent, pan-RAS-targeted DARPin elicits anti-tumor activity in a multimodal manner.
JO  - Molecular oncology
VL  - nn
SN  - 1574-7891
CY  - Hoboken, NJ
PB  - John Wiley & Sons, Inc.
M1  - DKFZ-2025-01240
SP  - nn
PY  - 2025
N1  - epub
AB  - 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.
KW  - Designed Ankyrin Repeat Protein (Other)
KW  - RAS (Other)
KW  - cancer (Other)
KW  - drug development (Other)
KW  - oncogene (Other)
KW  - small GTPase (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40517320
DO  - DOI:DOI:10.1002/1878-0261.70061
UR  - https://inrepo02.dkfz.de/record/302049
ER  -