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PXD060588

PXD060588 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleEGFR inhibitor-resistant lung cancers exhibit collateral sensitivity to a covalent, cysteine-independentKEAP1 oligomerizing molecular bridge
DescriptionTargeted 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 small molecule compound, 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.
HostingRepositoryMassIVE
AnnounceDate2025-02-07
AnnouncementXMLSubmission_2025-02-07_09:59:21.551.xml
DigitalObjectIdentifier
ReviewLevelNon peer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterHarrison Chong
SpeciesList scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationListCarbamidomethyl; TMTpro
InstrumentOrbitrap Eclipse
Dataset History
RevisionDatetimeStatusChangeLog Entry
02025-02-07 09:56:07ID requested
12025-02-07 09:59:21announced
Publication List
no publication
Keyword List
submitter keyword: DBIA, DatasetType:Proteomics
Contact List
Kris Wood
contact affiliationDuke University
contact emailkris.wood@duke.edu
lab head
Harrison Chong
contact affiliationMassachusetts General Hospital Cancer Center
contact emailhbchong@mgh.harvard.edu
dataset submitter
Full Dataset Link List
MassIVE dataset URI
Dataset FTP location
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