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Updated: Aug 9, 2025

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Exploiting the intrinsic misfolding propensity of the KRAS oncoprotein

Kobe Janssen1,2, Filip Claes3, Dido Van de Velde3

  • 1Switch Laboratory, VIB-KU Leuven Center for Brain and Disease Research, 3000 Leuven, Belgium.

Proceedings of the National Academy of Sciences of the United States of America
|February 22, 2023
PubMed

Insights

Synthetic peptides targeting aggregation-prone regions can misfold mutant KRAS (Kirsten rat sarcoma viral oncogene homolog), a cancer driver. This approach shows promise for inhibiting KRAS-driven tumors and offers a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Protein Chemistry

Background:

  • Mutant KRAS is a key driver in many cancers, posing a significant therapeutic challenge.
  • Classical small molecule drugs have limited success against KRAS, necessitating novel strategies.

Purpose of the Study:

  • To investigate the potential of exploiting KRAS's intrinsic aggregation-prone regions (APRs) for therapeutic targeting.
  • To develop synthetic peptides (Pept-ins™) that induce KRAS misfolding and inactivation.

Main Methods:

  • Identification and synthesis of peptides targeting KRAS APRs.
  • Assays to assess KRAS misfolding, loss of function, and antiproliferative effects in vitro and in cell-free systems.
  • In vivo studies using a syngeneic lung adenocarcinoma mouse model with mutant KRAS G12V.

Main Results:

  • Synthetic peptides derived from KRAS APRs successfully induced misfolding and loss of function of oncogenic KRAS.
  • Pept-ins™ demonstrated antiproliferative activity against various mutant KRAS cancer cell lines.
  • Tumor growth was abrogated in a mouse model of KRAS G12V-driven lung adenocarcinoma.

Conclusions:

  • The intrinsic misfolding propensity of KRAS can be therapeutically exploited for functional inactivation.
  • Peptide-based strategies targeting KRAS APRs represent a viable proof-of-concept for cancer therapy.
Keywords:
KRASoncogenepeptideprotein aggregationprotein folding

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