EGFR inhibitor-resistant lung cancers exhibit collateral sensitivity to a covalent, cysteine-independent KEAP1 oligomerizing molecular bridge

Targeted therapies have revolutionized cancer care. Unfortunately, most patients develop refractory, multifocal resistance to these therapies within a matter of months. Here, we demonstrate that the evolution of resistance to EGFR inhibitors in EGFR-mutant non-small cell lung cancer endows cells with hypersensitivity to a PAINS-like small molecule, MCB-613. Systematic proteomic, functional genomic, and biochemical studies revealed that MCB-613 binds KEAP1 in a covalent, cysteine-independent fashion, acting as a divalent molecular bridge that relies upon lysine residues in the KEAP1 dimerization domain to join monomers of KEAP1 together. Oligomerization of KEAP1 by MCB-613 sets into motion a fatal cascade of KEAP1 dysfunction, ROS accumulation, and ATF4/CHOP-dependent cell death. Together, these findings demonstrate that diverse models of EGFR inhibitor-resistant NSCLC share the common feature of elevated integrated stress response activity, and that a covalent molecular bridge which activates non-canonical KEAP1-ATF4 signaling can exploit this feature to select against resistance evolution.

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Publication Details

Journal
Nature Communications
Published
2026-01-14
DOI
https://doi.org/10.1038/s41467-026-68424-1
Primary Topic
Melanoma and MAPK Pathways
Type
article
Field-Weighted Citation Impact
0.00
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article

EGFR inhibitor-resistant lung cancers exhibit collateral sensitivity to a covalent, cysteine-independent KEAP1 oligomerizing molecular bridge

Samuel H. Gruber, Ella Livnah, Stefan Harry, Benjamin Mayro et al.
Nature Communications
Melanoma and MAPK Pathways
article

EGFR inhibitor-resistant lung cancers exhibit collateral sensitivity to a covalent, cysteine-independent KEAP1 oligomerizing molecular bridge

Samuel H. Gruber, Ella Livnah, Stefan Harry, Benjamin Mayro, Kévin Jubien-Girard, Tierney M. Hall, Cécile Favreau, Anthony R. Martin, Haley M. Hutchinson, Katherine R. Singleton, Shane T. Killarney, Christian Cerda-Smith, Alexandre Puissant, Guillaume Robert, Kayleigh N. Askin, Barr Tivon, Rachid Benhida, Christopher F. Bassil, Ann Marie Pendergast, Peter Winter, David M. Lonard, Kerry A. Dillon, Jacob P. Hoj, Ava Heffernan, Kris C. Wood, Liron Bar-Peled, Nir London, Caroline Teddy, Gray R. Anderson, Li Qin
article en

Abstract

Targeted therapies have revolutionized cancer care. Unfortunately, most patients develop refractory, multifocal resistance to these therapies within a matter of months. Here, we demonstrate that the evolution of resistance to EGFR inhibitors in EGFR-mutant non-small cell lung cancer endows cells with hypersensitivity to a PAINS-like small molecule, MCB-613. Systematic proteomic, functional genomic, and biochemical studies revealed that MCB-613 binds KEAP1 in a covalent, cysteine-independent fashion, acting as a divalent molecular bridge that relies upon lysine residues in the KEAP1 dimerization domain to join monomers of KEAP1 together. Oligomerization of KEAP1 by MCB-613 sets into motion a fatal cascade of KEAP1 dysfunction, ROS accumulation, and ATF4/CHOP-dependent cell death. Together, these findings demonstrate that diverse models of EGFR inhibitor-resistant NSCLC share the common feature of elevated integrated stress response activity, and that a covalent molecular bridge which activates non-canonical KEAP1-ATF4 signaling can exploit this feature to select against resistance evolution.

Nature CommunicationsVol. 17(1)
École Nationale Supérieure de Chimie de Montpellier (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Duke University (US), Baylor College of Medicine (US), Université de Montpellier (FR), Université Côte d'Azur (FR), Université Paris Cité (FR), Institut de Chimie de Nice (FR), Massachusetts General Hospital (US), Centre Méditerranéen de Médecine Moléculaire (FR), Université Mohammed VI Polytechnique (MA), Institut des Biomolécules Max Mousseron (FR), Center for Cancer Research (US), Weizmann Institute of Science (IL)
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Melanoma and MAPK Pathways
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