Language
English
Publication Date
11-21-2025
Journal
iScience
DOI
10.1016/j.isci.2025.113686
PMID
41244592
PMCID
PMC12616096
PubMedCentral® Posted Date
10-4-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Mutations in KRAS drive 88% of pancreatic ductal adenocarcinomas (PDAC) and up to 40% of low-grade serous ovarian cancers (LGSOC), making KRAS a long-standing therapeutic target. We previously showed that DIRAS3 binds RAS, forming heterodimers that disrupt RAS clustering and downstream MAPK signaling. Building on this, we developed conformationally constrained DIRAS3-derived peptides using two cyclization strategies and characterized them by NMR and biolayer interferometry. These cyclic peptides attenuate the interaction between KRAS and the BRAF RAS-binding domain, penetrate cells efficiently, and inhibit KRAS nanoclustering on the inner leaflet of the plasma membrane. Functionally, they reduce cell viability and suppress PDAC and LGSOC growth in cell culture and xenograft models. Our findings demonstrate that DIRAS3-based cyclic peptides represent a distinct strategy to directly inhibit oncogenic KRAS signaling and provide a promising framework for therapeutic development in KRAS-driven cancers.
Keywords
molecular biology, structural biology, cancer
Published Open-Access
yes
Recommended Citation
Gray, Joshua P; Bildik, Gamze; Kim, Ha-Neul; et al., "DIRAS3-Derived Cyclic Peptides Disrupt Kras-Raf Interaction and Kras Nanoclustering, Suppressing Kras-Driven Pancreatic and Ovarian Tumors" (2025). Faculty and Staff Publications. 5676.
https://digitalcommons.library.tmc.edu/baylor_docs/5676
Graphical Abstract
Included in
Allergy and Immunology Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Medical Molecular Biology Commons, Oncology Commons, Pathology Commons