PXD029719

PXD029719 is an original dataset announced via ProteomeXchange.

Title	Strategies to inhibit FGFR4 V550L-driven rhabdomyosarcoma
Description	Rhabdomyosarcoma (RMS) is a paediatric cancer driven either by a fusion protein (e.g. PAX3-FOXO1) or by mutations in key signalling molecules (e.g. RAS or FGFR4). Despite the latter giving potential for precision medicine approaches in RMS, there are no such treatments implemented in the clinic yet. In order to identify and test novel precision therapy strategies, appropriate cellular and mouse models are crucial. We have here thoroughly characterized a RMS patient-derived cell line model, RMS559, which harbours a FGFR4 V550L activating mutation with high allelic frequency (0.8). Importantly, we show that RMS559 cells are oncogenically dependent on FGFR4 signalling by treatment with the pan-FGFR inhibitor LY2874455. Phosphoproteomic analysis identified RAS/MAPK and PI3K/AKT as the major druggable signalling pathways downstream of FGFR V550L. Inhibitors against these pathways inhibited cell proliferation. Furthermore, we found that FGFR4 V550L is dependent on HSP90 and inhibitors targeting HSP90 efficiently restrain proliferation. Recently, FGFR4 specific inhibitors have been developed. While two of these, BLU-9931 and H3B-6527, did not efficiently inhibit FGFR4 V550L, probably because of the gatekeeper mutation (V550L), one of them, FGF401 inhibited FGFR4 V550L and cell proliferation at low nanomolar concentrations. Finally, we developed a mouse model using RMS559 cells and tested the in vivo efficacy of LY2874455 and FGF401. While LY2874455 inefficiently inhibited growth, FGF401 completely abrogated tumour growth in vivo.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:11:32.500.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sachin Singh
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-12 06:17:09	ID requested
1	2022-10-19 00:24:19	announced
⏵ 2	2023-11-14 08:11:33	announced	2023-11-14: Updated project metadata.

Fiorito E, Szybowska P, Haugsten EM, Kostas M, Ø, y GF, Wiedlocha A, Singh S, Nakken S, M, æ, landsmo GM, Fletcher JA, Meza-Zepeda LA, Wesche J, Strategies to inhibit FGFR4 V550L-driven rhabdomyosarcoma. Br J Cancer, 127(11):1939-1953(2022) [pubmed]

submitter keyword: proteomics, rhabdomyosarcoma,FGFR4, V550L

Jørgen Wesche
contact affiliation	Department of Tumor Biology, Institute for Cancer ResearchThe Norwegian Radium Hospital, Oslo University Hospital
contact email	jorgen.wesche@rr-research.no
lab head
Sachin Singh
contact affiliation	Proteomics core facility, Olso University hospital, Norway
contact email	sachin.kumar.singh@rr-research.no
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/2022/10/PXD029719

PRIDE project URI

• PRIDE
  1. PXD029719
     1. Label: PRIDE project
     2. Name: Strategies to inhibit FGFR4 V550L-driven rhabdomyosarcoma