EGFR Inhibitor-Resistant Lung Cancers Exhibit Collateral Sensitivity to a Covalent, Cysteine-Independent KEAP1 Oligomerizing Molecular Bridge

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

Language

English

Publication Date

1-14-2026

Journal

Nature Communications

DOI

10.1038/s41467-026-68424-1

PMID

41535280

PMCID

PMC12913772

PubMedCentral® Posted Date

1-14-2026

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Kelch-Like ECH-Associated Protein 1, Humans, ErbB Receptors, Lung Neoplasms, Drug Resistance, Neoplasm, Cysteine, Cell Line, Tumor, Animals, Activating Transcription Factor 4, Protein Kinase Inhibitors, Carcinoma, Non-Small-Cell Lung, Signal Transduction, Reactive Oxygen Species, Transcription Factor CHOP, Mice, Cancer therapeutic resistance, Target identification, Small molecules, Non-small-cell lung cancer, Target validation

Published Open-Access

yes

Recommended Citation

Bassil, Christopher F; Dillon, Kerry; Anderson, Gray R; et al., "EGFR Inhibitor-Resistant Lung Cancers Exhibit Collateral Sensitivity to a Covalent, Cysteine-Independent KEAP1 Oligomerizing Molecular Bridge" (2026). Faculty, Staff and Students Publications. 7057.
https://digitalcommons.library.tmc.edu/baylor_docs/7057