Authors
Kyle J Seamon, Yongxian Zhuang, Yu Chi Yang, Sujata Chakraborty, James Cregg, Aidan C A Tomlinson, Andrea Gould, Ethan Ahler, Benjamin J Maldonato, Jessica N Spradlin, Kristof Pota, Caroline Weller, Abby Marquez, Zhican Wang, Elena S Koltun, John E Knox, Adrian L Gill, Jacqueline A M Smith, Mallika Singh, Jingjing Jiang, David Wildes, Matthew Holderfield
Published in
Cancer discovery. Jun 22, 2026. Epub Jun 22, 2026.
Abstract
Covalent KRAS G12C inhibitors have changed the treatment landscape for NSCLC and CRC patients, but numerous RAS-mutant cancers lack approved targeted therapies. Here we describe RMC-8839, an oral RAS(ON) G13C-selective, covalent, tri-complex inhibitor that induced tumor regressions in selected KRAS G13C-mutant xenograft models. However, one-third of KRAS G13C-mutant human cancer cell lines in vitro showed incomplete RAS pathway suppression despite near-complete KRAS G13C engagement, suggesting a role for wild-type RAS(ON). We find that codon 13-mutant RAS differs from other KRAS mutations, exhibiting decreased stability, increased nucleotide exchange, and substantial intrinsic and GAP-stimulated GTP hydrolysis, which decreases oncogenicity. Furthermore, co-occurring RAS pathway mutations leading to increased wild-type RAS activation are enriched in codon 13 mutant tumors. Consistent with a role for wild-type RAS(ON) signaling, combination of RMC-8839 with a RAS(ON) multi-selective inhibitor resulted in deeper inhibition of KRAS G13C-mutant xenograft tumor growth than either inhibitor alone.
PMID:
42329095
Bibliographic data and abstract were imported from PubMed on 22 Jun 2026.
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