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PXD042572

PXD042572 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleThe effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer
DescriptionAXL is a receptor tyrosine kinase that is often overexpressed in cancers. It contributes to pathophysiology in cancer progression and therapeutic resistance, making it an emerging therapeutic target. The first-in-class AXL inhibitor bemcentinib (R428/BGB324) has been granted fast track designation by the U.S. Food and Drug Administration (FDA) in STK11-mutated advanced metastatic non-small cell lung cancer and was also reported to show selective sensitivity towards ovarian cancers (OC) with a Mesenchymal molecular subtype. In this study, we further explored AXL’s role in mediating DNA damage responses by using OC as a disease model. AXL inhibition using R428 resulted in the increase of DNA damage with the concurrent upregulation of DNA damage response signalling molecules. Furthermore, AXL inhibition rendered cells more sensitive to the inhibition of ATR, a crucial mediator for replication stress. Combinatory use of AXL and ATR inhibitors showed additive effects in OC. Through SILAC co-immunoprecipitation mass spectrometry, we identified a novel binding partner of AXL, SAM68, whose loss in OC cells harboured phenotypes in DNA damage responses similar to AXL inhibition. In addition, AXL- and SAM68-deficiency or R428 treatment induced elevated levels of cholesterol and upregulated genes in the cholesterol biosynthesis pathway. There might be a novel protective role of cholesterol in shielding cancer cells against DNA damage induced by AXL inhibition or SMA68 deficiency.  
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_05:49:40.232.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterDennis Kappei
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList6x(13)C; 6x(13)C
InstrumentQ Exactive HF
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-05-31 04:16:48ID requested
12024-10-07 13:49:16announced
22024-10-22 05:49:40announced2024-10-22: Updated project metadata.
Publication List
10.1038/S42003-023-05045-0;
Keyword List
submitter keyword: AXL, Combination treatment, DNA damage, Cholesterol biosynthesis
Contact List
Dennis Kappei
contact affiliationCancer Science Institute of Singapore (CSI), National University of Singapore (NUS)
contact emaildennis.kappei@nus.edu.sg
lab head
Dennis Kappei
contact affiliationCancer Science Institute of Singapore
contact emaildennis.kappei@nus.edu.sg
dataset submitter
Full Dataset Link List
Dataset FTP location
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