PXD035131

PXD035131 is an original dataset announced via ProteomeXchange.

Title	Therapeutic targeting of ATR in alveolar rhabdomyosarcoma
Description	Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS) remain dismal. Here we show that PAX3-FOXO1-expressing ARMS cells are sensitive to pharmacological ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Expression of PAX3-FOXO1 in muscle progenitor cells is not only sufficient to increase sensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibit increased sensitivity to structurally diverse inhibitors of ATR. Mechanistically, ATR inhibition leads to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increases sensitivity of ARMS cells to PARP1 inhibition in vitro, and combined treatment with ATR and PARP1 inhibitors induces complete regression of primary patient-derived ARMS xenografts in vivo. Lastly, a genome-wide CRISPR activation screen (CRISPRa) in combination with transcriptional analyses of ATR inhibitor resistant ARMS cells identifies the RAS-MAPK pathway and its targets, the FOS gene family, as inducers of resistance to ATR inhibition. Our findings provide a rationale for upcoming biomarker-driven clinical trials of ATR inhibitors in patients suffering from ARMS.
HostingRepository	jPOST
AnnounceDate	2022-07-11
AnnouncementXML	Submission_2024-03-12_19:35:44.197.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Koshi Imami
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	S-carboxamidomethyl-L-cysteine; alpha-amino acetylated residue; L-methionine sulfoxide; O-phospho-L-serine; O-phospho-L-threonine; O4'-phospho-L-tyrosine; deamidated L-glutamine; deamidated L-asparagine
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-07-06 17:42:50	ID requested
1	2022-07-11 00:52:55	announced
2	2022-09-18 02:42:34	announced	2022-09-18: Updated FTP location.
⏵ 3	2024-03-12 19:35:45	announced	2024-03-13: Updated PubMed.

Dorado Garc, í, a H, Pusch F, Bei Y, von Stebut J, Ib, á, ñ, ez G, Guillan K, Imami K, G, ü, rgen D, Rolff J, Helmsauer K, Meyer-Liesener S, Timme N, Bardinet V, Chamorro Gonz, á, lez R, MacArthur IC, Chen CY, Schulz J, Wengner AM, Furth C, Lala B, Eggert A, Seifert G, Hundsoerfer P, Kirchner M, Mertins P, Selbach M, Lissat A, Dubois F, Horst D, Schulte JH, Spuler S, You D, Dela Cruz F, Kung AL, Haase K, DiVirgilio M, Scheer M, Ortiz MV, Henssen AG, Therapeutic targeting of ATR in alveolar rhabdomyosarcoma. Nat Commun, 13(1):4297(2022) [pubmed]

submitter keyword: phosphoproteomics

Anton Henssen
lab head
Koshi Imami
contact affiliation	RIKEN
dataset submitter

jPOST dataset URI

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.jpostdb.org/JPST001683/