PXD034228

PXD034228 is an original dataset announced via ProteomeXchange.

Title	TKI-resistant T790M EGFR Mutation Rewired EGFR Translocation Routes through Switching Interactome in Non-Small Cell Lung Cancer
Description	Epidermal growth factor receptor (EGFR) harboring active mutations, Del19 and L858R, are most common oncogenic mutations in in non-small cell lung cancer (NSCLC) patients. The preferred treatment at first line is tyrosine kinase inhibitor (TKI) administration while the TKI-resistance usually develops because of acquiring the secondary EGFR T790M mutant. Protein-protein interactions (PPIs) constitute the signaling scaffold and thus aberrant PPIs ascribed to mutations often results in dysregulations of downstream signaling cascades. Affinity purification coupled mass spectrometry (AP-MS) was utilized to characterize the EGFR PPIs in four NSCLC cells which carry different EGFR subtypes representing as TKI-sensitive and -resistant models in this study. The EGFR interactomes of TKI-resistant NSCLC cells presented higher diversity of subcellular distribution as well as the hyperactive EGFR trafficking. Furthermore, gefitinib perturbation activated autophagy-mediated EGFR degradation in TKI-resistant NSCLC models and inhibiting autophagy process indeed reduced the TKI-resistance against gefitinib as cytotoxicity was significantly improved. Alternatively, gefitinib induced EGFR translocation toward cell periphery through Rab7 ubiquitination in TKI-sensitive models which may confer TKIs more chance to suppress EGFR activity. In brief, acquired T790M EGFR mutation rewired the EGFR inherent interactomes and thus guided EGFR moving toward distinct trafficking routes, EGFR recycling or autophagy-mediated degradation, in response to TKI insult in TKI-sensitive and -resistant NSCLC cells. These finding suggest that manipulation or combined autophagy inhibition may provide us a novel therapeutic strategy to manage TKI-resistance and tumor relapse in NSCLC.
HostingRepository	jPOST
AnnounceDate	2023-05-31
AnnouncementXML	Submission_2023-05-30_08:00:06.562.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Miao-Hsia Lin
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	S-carboxamidomethyl-L-cysteine; alpha-amino acetylated residue; L-methionine sulfoxide
Instrument	TripleTOF 5600

Revision	Datetime	Status	ChangeLog Entry
0	2022-05-31 02:13:05	ID requested
⏵ 1	2023-05-30 08:00:06	announced

Dataset with its publication pending

submitter keyword: Epidermal growth factor receptor (EGFR), non-small cell lung cancer (NSCLC), interactome, tyrosine kinase inhibitor (TKI), T790M mutation, autophagy

Yu-Ju Chen
lab head
Miao-Hsia Lin
contact affiliation	Institute of Chemistry, Academia Sinica
dataset submitter

jPOST dataset URI

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