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

Jonas N Kapp1, Wouter P R Verdurmen1, Jonas V Schaefer1

  • 1Department of Biochemistry, University of Zurich, Switzerland.

Molecular Oncology
|June 15, 2025
PubMed

Insights

A novel Designed Ankyrin Repeat Protein (DARPin) targets KRAS oncoprotein, blocking its activation and downstream signaling. This nucleotide-independent approach effectively reduced cancer cell proliferation and induced tumor regression in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRAS oncoprotein is a key driver in lung, pancreatic, and colorectal cancers.
  • Targeting KRAS has been challenging, with limited understanding of nucleotide-state specificity and RAS nanoclustering.
  • Existing KRAS-targeted therapeutics are in early clinical trials.

Purpose of the Study:

  • To develop and characterize a novel pan-RAS, nucleotide-independent inhibitor.
  • To investigate the effects of targeting the RAS switch I/II region on KRAS activation and downstream signaling.
  • To evaluate the therapeutic potential of the developed inhibitor in preclinical cancer models.

Main Methods:

  • Development of a Designed Ankyrin Repeat Protein (DARPin) targeting the RAS switch I/II region.
  • Assessment of DARPin binding affinity and nucleotide-state independence.
  • Evaluation of DARPin's interference with SOS-mediated activation and effector interactions.
  • Analysis of DARPin's impact on KRAS nanoclustering.
  • In vitro assessment of proliferation and anchorage-independent growth in RAS-dependent cell lines.
  • In vivo evaluation of DARPin efficacy in a colorectal xenograft model.

Main Results:

  • A novel DARPin, '784_F5', was developed with low nanomolar affinity for RAS, independent of GDP/GTP binding.
  • '784_F5' interferes with SOS-mediated activation, RAS effector interactions, and KRAS nanoclustering.
  • The DARPin potently blocked downstream signaling, significantly reducing proliferation and anchorage-independent growth in cancer cell lines.
  • Expression of '784_F5' led to tumor regression in a colorectal xenograft model.

Conclusions:

  • The developed pan-RAS, nucleotide-independent DARPin ('784_F5') effectively inhibits KRAS signaling.
  • This approach demonstrates potential for treating KRAS-driven cancers by targeting a conserved RAS structural element.
  • '784_F5' warrants further investigation and development as a novel cancer therapeutic.
Keywords:
Designed Ankyrin Repeat ProteinRAScancerdrug developmentoncogenesmall GTPase

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