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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月14日

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  • 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

摘要

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.