PXD071547

PXD071547 is an original dataset announced via ProteomeXchange.

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	PRIDE
AnnounceDate	2025-12-07
AnnouncementXML	Submission_2025-12-07_15:44:31.807.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD071547
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Christopher Bassil
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Velos Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-03 15:52:53	ID requested
⏵ 1	2025-12-07 15:44:32	announced

10.6019/PXD071547;

submitter keyword: KEAP1, MCB-613,EGFR-mutant non-small cell lung cancer

Kris Cameron Wood
contact affiliation	Department of Pharmacology and Cancer Biology Duke University School of Medicine Durham, North Carolina
contact email	kris.wood@duke.edu
lab head
Christopher Bassil
contact affiliation	Duke University Hospital
contact email	christopher.bassil@duke.edu
dataset submitter

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://ftp.pride.ebi.ac.uk/pride/data/archive/2025/12/PXD071547

PRIDE project URI

• PRIDE
  1. PXD071547
     1. Label: PRIDE project
     2. Name: EGFR inhibitor-resistant lung cancers exhibit collateral sensitivity to a covalent, cysteine-independentKEAP1 oligomerizing molecular bridge