PXD071008

PXD071008 is an original dataset announced via ProteomeXchange.

Title	Lipid metabolism drives osimertinib resistance in non-small cell lung cancer
Description	Non-small-cell lung cancer (NSCLC) accounts for more than 80 % of lung cancer cases. Epidermal growth factor receptor mutations (EGFRm) occur in 15 % and 40 % of NSCLC in Western and Asian populations, respectively. Current treatment for advanced NSCLC targets EGFRm with tyrosine kinase inhibitors (TKIs). Osimertinib is a third generation EGFR-TKI now used as a first-line treatment in advanced/metastatic NSCLC, however drug resistance frequently develops. Dysregulation of metabolism has been suggested to play a role in development of drug resistance. Here, we investigated the role of lipid metabolism in the development of osimertinib resistance (OR) using pharmacologically-induced resistant cellular models. We used a multi-omics approach, combining lipidomics with proteomics analyses. We found alterations in processes relating to metabolism, including dysregulated sphingolipid metabolism, lipid peroxidation and ferroptosis. In particular, we identified that OR lines reduce free ceramides in favour of complex glycosphingolipids. Mechanistically, this metabolic shift avoids ceramide-mediated apoptosis via caspase 3 activation. Importantly, when we combined osimertinib with D-PDMP, an inhibitor of the key enzyme responsible for the conversion of ceramide to glucosylceramide, we increased sensitivity to osimertinib. Overall, we have identified the glycosphingolipid metabolic pathway as a potential therapeutic target to reinstate sensitivity to osimertinib in NSCLC.
HostingRepository	PRIDE
AnnounceDate	2026-03-03
AnnouncementXML	Submission_2026-03-03_04:42:37.949.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alex Montoya
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	2-pyrrolidone-5-carboxylic acid (Gln); monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 240

Revision	Datetime	Status	ChangeLog Entry
0	2025-11-20 13:18:58	ID requested
⏵ 1	2026-03-03 04:42:38	announced

Dataset with its publication pending

submitter keyword: Nonsmall-cell lung cancer

lipidomics

glycosphingolipid

ceramide

sphingolipid, drug resistance

multi-omics

glucosylceramidase

Dr Zoe Hall
contact affiliation	Imperial College London
contact email	zoe.hall@imperial.ac.uk
lab head
Alex Montoya
contact affiliation	London Institute of Medical Sciences
contact email	proteomics@lms.mrc.ac.uk
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/2026/03/PXD071008

PRIDE project URI

• PRIDE
  1. PXD071008
     1. Label: PRIDE project
     2. Name: Lipid metabolism drives osimertinib resistance in non-small cell lung cancer