PXD060588
PXD060588 is an original dataset announced via ProteomeXchange.
Dataset Summary
Title | EGFR inhibitor-resistant lung cancers exhibit collateral sensitivity to a covalent, cysteine-independentKEAP1 oligomerizing molecular bridge |
Description | 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 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. |
HostingRepository | MassIVE |
AnnounceDate | 2025-02-07 |
AnnouncementXML | Submission_2025-02-07_09:59:21.551.xml |
DigitalObjectIdentifier | |
ReviewLevel | Non peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Supported dataset by repository |
PrimarySubmitter | Harrison Chong |
SpeciesList | scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606; |
ModificationList | Carbamidomethyl; TMTpro |
Instrument | Orbitrap Eclipse |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
---|---|---|---|
0 | 2025-02-07 09:56:07 | ID requested | |
⏵ 1 | 2025-02-07 09:59:21 | announced |
Publication List
no publication |
Keyword List
submitter keyword: DBIA, DatasetType:Proteomics |
Contact List
Kris Wood | |
---|---|
contact affiliation | Duke University |
contact email | kris.wood@duke.edu |
lab head | |
Harrison Chong | |
contact affiliation | Massachusetts General Hospital Cancer Center |
contact email | hbchong@mgh.harvard.edu |
dataset submitter |
Full Dataset Link List
MassIVE dataset URI |
Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://massive.ucsd.edu/v09/MSV000097077/ |