Selective Inhibition of KRASG13C Reveals an Increased Dependence on Wild-type RAS Isoforms in Codon 13 RAS-Mutant Cancers
- 1Revolution Medicines, Inc., Redwood City, California.
Abstract
Covalent KRASG12C inhibitors have changed the treatment landscape for patients with non–small cell lung cancer and colorectal cancer, but numerous RAS-mutant cancers lack approved targeted therapies. In this study, we describe RMC-8839, an oral RAS(ON) G13C-selective, covalent, tricomplex inhibitor that induced tumor regressions in selected KRASG13C-mutant xenograft models. However, one third of KRASG13C-mutant human cancer cell lines in vitro showed incomplete RAS pathway suppression despite near-complete KRASG13C 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 guanosine triphosphatase-activating protein–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, the combination of RMC-8839 with a RAS(ON) multiselective inhibitor resulted in deeper inhibition of KRASG13C-mutant xenograft tumor growth than either inhibitor alone.
Significance:: An enhanced understanding of the underlying biology of RAS mutations is critical to inform therapeutic strategies. Our preclinical data highlight that codon 13 mutant tumors are more reliant on wild-type RAS signaling than codon 12 tumors and demonstrate that this can be addressed by combining RAS(ON) G13C-selective and multiselective inhibitors.
See related commentary by Araujo and Skoulidi, p. 2206
See related article by McDaid et al., p. 2274
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BibTeX
@article{seamon2026selective,
title = {{Selective Inhibition of KRASG13C Reveals an Increased Dependence on Wild-type RAS Isoforms in Codon 13 RAS-Mutant Cancers}},
author = {Kyle J. Seamon and Yongxian Zhuang and Yu Chi Yang and Sujata Chakraborty and James Cregg and Aidan C.A. Tomlinson and Andrea Gould and Ethan Ahler and Benjamin J. Maldonato and Jessica N. Spradlin and Kristof Pota and Caroline Weller and Abby Marquez and Zhican Wang and Elena S. Koltun and John E. Knox and Adrian L. Gill and Jacqueline A.M. Smith and Mallika Singh and Jingjing Jiang and David Wildes and Matthew Holderfield},
journal = {Cancer Discovery},
year = {2026},
month = jun,
doi = {10.1158/2159-8290.cd-25-0886},
url = {https://doi.org/10.1158/2159-8290.cd-25-0886},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Selective Inhibition of KRASG13C Reveals an Increased Dependence on Wild-type RAS Isoforms in Codon 13 RAS-Mutant Cancers
AU - Kyle J. Seamon
AU - Yongxian Zhuang
AU - Yu Chi Yang
AU - Sujata Chakraborty
AU - James Cregg
AU - Aidan C.A. Tomlinson
AU - Andrea Gould
AU - Ethan Ahler
AU - Benjamin J. Maldonato
AU - Jessica N. Spradlin
AU - Kristof Pota
AU - Caroline Weller
AU - Abby Marquez
AU - Zhican Wang
AU - Elena S. Koltun
AU - John E. Knox
AU - Adrian L. Gill
AU - Jacqueline A.M. Smith
AU - Mallika Singh
AU - Jingjing Jiang
AU - David Wildes
AU - Matthew Holderfield
PY - 2026
DA - 2026/06/22
JO - Cancer Discovery
DO - 10.1158/2159-8290.cd-25-0886
UR - https://doi.org/10.1158/2159-8290.cd-25-0886
AB - Covalent KRASG12C inhibitors have changed the treatment landscape for patients with non–small cell lung cancer and colorectal cancer, but numerous RAS-mutant cancers lack approved targeted therapies. In this study, we describe RMC-8839, an oral RAS(ON) G13C-selective, covalent, tricomplex inhibitor that induced tumor regressions in selected KRASG13C-mutant xenograft models. However, one third of KRASG13C-mutant human cancer cell lines in vitro showed incomplete RAS pathway suppression despite near-complete KRASG13C 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 guanosine triphosphatase-activating protein–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, the combination of RMC-8839 with a RAS(ON) multiselective inhibitor resulted in deeper inhibition of KRASG13C-mutant xenograft tumor growth than either inhibitor alone. Significance:: An enhanced understanding of the underlying biology of RAS mutations is critical to inform therapeutic strategies. Our preclinical data highlight that codon 13 mutant tumors are more reliant on wild-type RAS signaling than codon 12 tumors and demonstrate that this can be addressed by combining RAS(ON) G13C-selective and multiselective inhibitors. See related commentary by Araujo and Skoulidi, p. 2206 See related article by McDaid et al., p. 2274
SN - 2159-8274
SN - 2159-8290
ER -