PXD013461

PXD013461 is an original dataset announced via ProteomeXchange.

Title	Fusion partners influence cellular and molecular phenotypes of oncogenic BRAF fusions
Description	Fusion genes can be oncogenic drivers in a variety of cancer types and represent potential targets for targeted therapy. The BRAF gene is frequently involved in oncogenic fusions, with fusion frequencies of 0.2-3% throughout different cancers. However, BRAF fusions rarely occur in the same gene configuration, potentially challenging personalized therapy design. In particular, the influence that is imposed by the wide variety of fusion partners on the oncogenic role of BRAF during tumor growth and drug response is unknown. Here, we used patient-derived colorectal cancer organoids to functionally characterize and cross-compare previously identified BRAF fusions containing various partner genes (AGAP3, DLG1 and TRIM24) with respect to cellular behaviour, downstream signaling activation and response to targeted therapies. We demonstrate that 5’ partner choice of BRAF fusions affects their subcellular localization and intracellular signaling capacity. In particular the DLG1-BRAF fusion protein showed distinct localization to the plasma membrane and exhibited increased activation of downstream MAPK signaling under unperturbed conditions. Moreover, phosphoproteomics and RNA sequencing identified distinct subsets of affected signaling pathways and altered gene expression of BRAF fusions. The different BRAF fusions exhibited varying sensitivities to simultaneous targeted inhibition of MEK and the EGF receptor family. However, all BRAF fusions conveyed resistance to targeted monotherapy against the EGF receptor family, suggesting that BRAF fusions should be screened alongside other MAPK pathway alterations to identify mCRC patients to exclude from cetuximab treatment
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:55:22.854.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Harmjan Vos
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2019-04-11 05:42:51	ID requested
1	2020-01-17 05:54:35	announced
⏵ 2	2024-10-22 04:55:25	announced	2024-10-22: Updated project metadata.

10.1158/1541-7786.mcr-19-0529;

Stangl C, Post JB, van Roosmalen MJ, Hami N, Verlaan-Klink I, Vos HR, van Es RM, Koudijs MJ, Voest EE, Snippert HJG, Kloosterman WP, Gene Fusions Confer Resistance to EGFR-Targeted Therapy via Differential Modulation of BRAF Activity. Mol Cancer Res, 18(4):537-548(2020) [pubmed]

submitter keyword: resistance,CRC, Fusion Partner, Organoids, BRAF, signaling, Fusion Genes

Hugo Snippert
contact affiliation	Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, CX Utrecht, the Netherlands
contact email	H.J.G.Snippert@umcutrecht.nl
lab head
Harmjan Vos
contact affiliation	University Medical Center Utrecht Dept. Molecular Cancer Research
contact email	h.r.vos-3@umcutrecht.nl
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/2020/01/PXD013461

PRIDE project URI

• PRIDE
  1. PXD013461
     1. Label: PRIDE project
     2. Name: Fusion partners influence cellular and molecular phenotypes of oncogenic BRAF fusions