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.
| Original language | English |
|---|---|
| Article number | 1726 |
| Journal | Nature Communications |
| Volume | 17 |
| DOIs | |
| Publication status | Published - 14 Jan 2026 |
Funding
We would like to thank Pasi Janne (Harvard Medical School) for the PFR3, GR4, and WZR12 cell lines. We also thank Aaron Hata (Harvard Medical School) for the patient-derived MGH134 cell line. We thank Bert O’Malley (Baylor College of Medicine) for MCB-613 and for his continued support and feedback on this project. We thank the Duke Functional Genomics Core for their assistance with high-throughput pharmacologic screening. We thank Ross Tomaino (Taplin Mass Spectrometry Facility, Harvard Medical School) and Erik Soderblom (Proteomics and Metabolics Core Facility, Duke University School of Medicine) for their input and assistance on proteomic studies. We thank Aurélien Lebrun (Plateforme d’analyses et caractérisation, P.A.C. Balard, Université Montpellier) for his NMR characterization of ARM-143. Finally, we would like to thank Kevin H. Lin and Justine C. Rutter for their invaluable advice and support along the way. This work was supported by the NIH (R01CA263593 to K.C.W., R01CA246133 to A.M.P., P30CA014236 to K.C.W. and A.M.P., 1R38AI140297 to C.F.B., R37CA260062 to L.B.-P., R21CA226082 to L.B.-P., K00CA245732-04 to J.H., 5T32GM007105, F31CA243293, and F99CA264162 to B.M., F30CA247323 to C.C.S., and F31CA195967 to P.S.W.), the DOD (W81XWH-21-1-0362 and HT9425-24-1-0338 to K.C.W.), the National Science Foundation (DGE-1106401 to G.R.A.), the American Cancer Society (PF-23-1018904-01-ET to S.A.H.), the Duke Medical Scientist Training Program (T32GM007171 to C.F.B., C.C.S., and S.T.K.), the Duke Graduate School (to C.F.B.), the Triangle Center for Evolutionary Medicine (to C.F.B.), the Amgen Scholars Program (to S.G.), the French National Center for Scientific Research (to A.R.M.), the Melanoma Research Alliance (to L.B.-P.), the Ludwig Cancer Center of Harvard Medical School (to L.B.-P.), Lungevity (to L.B.-P.), ALK Positive (to L.B.-P.), V-Foundation for Cancer Research (to L.B.-P.), Mary Kay Foundation (to L.B.-P.), Paula and Rodger Riney Foundation (to L.B.-P.), the PEW-Stewart Trusts (to L.B.-P.), and Lisa and Mark Schwartz (to L.B.-P.).
All Science Journal Classification (ASJC) codes
- General Chemistry
- General Biochemistry,Genetics and Molecular Biology
- General
- General Physics and Astronomy
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