EGFR inhibitor-resistant lung cancers exhibit collateral sensitivity to a covalent, cysteine-independent KEAP1 oligomerizing molecular bridge
Year: 2026
Type: article
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. EGFR inhibitors are standard of care in patients with EGFR-mutant non-small cell lung cancer (NSCLC) but resistance often develops. Here the authors report that the evolution of EGFR inhibitor resistance in EGFR-mutant NSCLC results in a sensitivity to the compound, MCB-613, and investigate the underlying mechanism of action.
Source: Nature Communications
Authors: Christopher F. Bassil, Kerry Dillon, Gray R. Anderson, Benjamin Mayro, Kayleigh N. Askin, Peter S. Winter, Stefan Harry, Samuel Gruber, Tierney M. Hall, Jacob P. Hoj, Christian Cerda-Smith, Haley M. Hutchinson, Shane T. Killarney, Ava Heffernan, Caroline Teddy, Katherine R. Singleton, Li Qin, Kévin Jubien-Girard, Cécile Favreau, Guillaume Robert, Barr Tivon, Ella Livnah, Nir London, Rachid Benhida, Patrick Auberger, Ann Marie Pendergast, Liron Bar-Peled, David M. Lonard, Anthony R. Martin, Alexandre Puissant, Kris C. Wood
Institutions: Duke University, Massachusetts General Hospital, Baylor College of Medicine, Centre National de la Recherche Scientifique, Institut de Chimie de Nice, Université Nice Sophia Antipolis, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire, Weizmann Institute of Science, Université Mohammed VI Polytechnique, École Nationale Supérieure de Chimie de Montpellier, Université de Montpellier, Institut des Biomolécules Max Mousseron, Inserm, Université Paris Cité, Institut de recherche Saint-Louis
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funder: National Institutes of Health
OpenAlex ID: W7124179573