PXD042572-1

PXD042572 is an original dataset announced via ProteomeXchange.

Title	The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer
Description	AXL 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.
HostingRepository	PRIDE
AnnounceDate	2024-10-07
AnnouncementXML	Submission_2024-10-07_13:49:16.337.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dennis Kappei
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	6x(13)C; 6x(13)C
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-05-31 04:16:48	ID requested
⏵ 1	2024-10-07 13:49:16	announced
2	2024-10-22 05:49:40	announced	2024-10-22: Updated project metadata.

10.1038/S42003-023-05045-0;

submitter keyword: AXL, Combination treatment, DNA damage, Cholesterol biosynthesis

Dennis Kappei
contact affiliation	Cancer Science Institute of Singapore (CSI), National University of Singapore (NUS)
contact email	dennis.kappei@nus.edu.sg
lab head
Dennis Kappei
contact affiliation	Cancer Science Institute of Singapore
contact email	dennis.kappei@nus.edu.sg
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD042572
     1. Label: PRIDE project
     2. Name: The effect of inhibition of receptor tyrosine kinase AXL on DNA damage response in ovarian cancer