Targeting KRAS Codon 13 Mutations Using Direct Combination Approaches in Non–Small Cell Lung Cancer
14 affiliations
- 1Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United Kingdom.
- 2Cell Signaling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom.
- 3The Christie NHS Foundation Trust, Manchester, United Kingdom.
- 4Revolution Medicines, Redwood City, California.
- 5Department of Biochemistry and Molecular Biology, Faculty of Chemical Sciences, Complutense University of Madrid, Madrid, Spain.
- 6Cancer Research UK Lung Centre of Excellence, Manchester, United Kingdom.
- 7Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France.
- 8Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
- 9Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), ICO-HUB Comprehensive Cancer Center, L’Hospitalet de Llobregat, Spain.
- 10Clinical Discovery Bioinformatics, Université Paris-Saclay, Institut Gustave Roussy, IHU PRISM, Villejuif, France.
- 11Inflammation and Cancer Plasticity Laboratory, Université Paris-Saclay, Inserm U981, Institut Gustave Roussy, IHU PRISM, Villejuif, France.
- 12Institut Gustave Roussy, Inserm, Prédicteurs Moléculaires et Nouvelles Cibles en Oncologie (U981), Université Paris-Saclay, Villejuif, France.
- 13Department of Pneumology, Thoracic Oncology Unit, AP-HP, Groupe Hospitalier HUPC, Hôpital Cochin, Paris, France.
- 14Centre de Recherche des Cordeliers, UMRS 1138 Complement, Inflammation and Cancer, Université Paris Descartes, Paris, France.
Abstract
Direct inhibitors of KRASG12C are now used as standard-of-care therapy in KRASG12C-mutant non–small cell lung cancer (NSCLC), but less is understood about the molecular mechanisms and consequent treatment vulnerabilities of KRAS codon 13 mutations in this setting. In this study, we characterized the tumorigenic properties of NSCLC harboring KRASG13X in a large multinational cohort of patients with NSCLC and in preclinical models of KRASG13X NSCLC. Induction of KRASG13C or KRASG13D expression confers reduced oncopotency compared with allele-specific controls affecting KRAS codon 12, particularly KRASG13C. We identified functionally relevant comutations in KRASG13X NSCLC, including KEAP1, STK11, BRAF, and NF1. The novel RAS(ON) G13C-selective inhibitor, RMC-8839, reduces viability in a panel of KRASG13C NSCLC cell models. To determine combination partners that enhance RAS(ON) mutant-selective inhibition, a drug repurposing screen revealed that KRASG13C models are selectively vulnerable to chemotherapy. Combination of docetaxel with RMC-8839 demonstrated robust antiproliferative activity in KRASG13C-driven NSCLC models in vitro and in vivo.
Significance:: We characterize the second most common KRAS mutational hotspot in NSCLC after codon 12, KRASG13X, from tumor initiation to advanced disease. KRASG13C is a novel, directly targetable subset of NSCLC, with vulnerability to the combination of chemotherapeutics and the mutant-selective RAS(ON) inhibitor RMC-8839, a finding immediately relevant to patient care.
See related commentary by Araujo and Skoulidi, p. 2206
See related article by Seamon et al., p. 2256
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BibTeX
@article{mcdaid2026targeting,
title = {{Targeting KRAS Codon 13 Mutations Using Direct Combination Approaches in Non–Small Cell Lung Cancer}},
author = {William J. McDaid and Helen Adderley and Paolo D. d’Arienzo and Ana S. Parreira and Laura C. Woodhouse and Yongxian Zhuang and Sonia Castillo-Lluva and Kirsten L. Tinsley and James Cooksedge and Martin J. Baker and Joshua Searle and Katherine D. Brown and Mathew Carter and Mihaela Aldea and Arianna Marinello and Jacqueline V. Aredo and Nadia Gomez Serra and Maria Bisbe and Philip East and Sophie de Carné Trécesson and Fabrice Barlesi and Marie Wislez and Benjamin Besse and Heather A. Wakelee and Ernest Nadal and Fiona Blackhall and David C. Wedge and Matthew Holderfield and Jacqueline A.M. Smith and Mallika Singh and Kyle J. Seamon and Angeliki Malliri and Colin R. Lindsay},
journal = {Cancer Discovery},
year = {2026},
month = jun,
doi = {10.1158/2159-8290.cd-25-0884},
url = {https://doi.org/10.1158/2159-8290.cd-25-0884},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting KRAS Codon 13 Mutations Using Direct Combination Approaches in Non–Small Cell Lung Cancer
AU - William J. McDaid
AU - Helen Adderley
AU - Paolo D. d’Arienzo
AU - Ana S. Parreira
AU - Laura C. Woodhouse
AU - Yongxian Zhuang
AU - Sonia Castillo-Lluva
AU - Kirsten L. Tinsley
AU - James Cooksedge
AU - Martin J. Baker
AU - Joshua Searle
AU - Katherine D. Brown
AU - Mathew Carter
AU - Mihaela Aldea
AU - Arianna Marinello
AU - Jacqueline V. Aredo
AU - Nadia Gomez Serra
AU - Maria Bisbe
AU - Philip East
AU - Sophie de Carné Trécesson
AU - Fabrice Barlesi
AU - Marie Wislez
AU - Benjamin Besse
AU - Heather A. Wakelee
AU - Ernest Nadal
AU - Fiona Blackhall
AU - David C. Wedge
AU - Matthew Holderfield
AU - Jacqueline A.M. Smith
AU - Mallika Singh
AU - Kyle J. Seamon
AU - Angeliki Malliri
AU - Colin R. Lindsay
PY - 2026
DA - 2026/06/22
JO - Cancer Discovery
DO - 10.1158/2159-8290.cd-25-0884
UR - https://doi.org/10.1158/2159-8290.cd-25-0884
AB - Direct inhibitors of KRASG12C are now used as standard-of-care therapy in KRASG12C-mutant non–small cell lung cancer (NSCLC), but less is understood about the molecular mechanisms and consequent treatment vulnerabilities of KRAS codon 13 mutations in this setting. In this study, we characterized the tumorigenic properties of NSCLC harboring KRASG13X in a large multinational cohort of patients with NSCLC and in preclinical models of KRASG13X NSCLC. Induction of KRASG13C or KRASG13D expression confers reduced oncopotency compared with allele-specific controls affecting KRAS codon 12, particularly KRASG13C. We identified functionally relevant comutations in KRASG13X NSCLC, including KEAP1, STK11, BRAF, and NF1. The novel RAS(ON) G13C-selective inhibitor, RMC-8839, reduces viability in a panel of KRASG13C NSCLC cell models. To determine combination partners that enhance RAS(ON) mutant-selective inhibition, a drug repurposing screen revealed that KRASG13C models are selectively vulnerable to chemotherapy. Combination of docetaxel with RMC-8839 demonstrated robust antiproliferative activity in KRASG13C-driven NSCLC models in vitro and in vivo. Significance:: We characterize the second most common KRAS mutational hotspot in NSCLC after codon 12, KRASG13X, from tumor initiation to advanced disease. KRASG13C is a novel, directly targetable subset of NSCLC, with vulnerability to the combination of chemotherapeutics and the mutant-selective RAS(ON) inhibitor RMC-8839, a finding immediately relevant to patient care. See related commentary by Araujo and Skoulidi, p. 2206 See related article by Seamon et al., p. 2256
SN - 2159-8274
SN - 2159-8290
ER -