PXD027187-1

PXD027187 is an original dataset announced via ProteomeXchange.

Title	ATR inhibition enables complete tumour regression in ALK-driven NB mouse models
Description	High-risk neuroblastoma (NB) often involves amplification of the neural MYC (MYCN) oncogene as well as mutations in ALK. Currently, high-risk NB presents significant clinical challenges, and additional therapeutic options are needed. Oncogenes such as MYCN and ALK result in increased replication stress in cancer cells, offering one such therapeutically exploitable option. Here, we followed up on earlier phosphoproteomic analyses that identified ATR activity in ALK-driven NB cell lines. We tested several ATR inhibitors, identifying BAY 1895344 as the most potent inhibitor of NB cell growth and proliferation. Using RNA-Seq, proteomics and phosphoproteomics we characterized the response of NB cells and tumours to ATR inhibition, identifying key components of the DNA damage response (DDR) as well as ATRX, MYCN, E2F and DCK among other ATR targets in NB cells. ATR inhibition with BAY 1895344 also produced robust responses in mouse NB models. Remarkably, a 2 week protocol combining ATR and ALK inhibition led to complete regression of NB tumours in two independent NB genetically modified mouse tumour models. These results suggest that NB patients, particularly in high-risk groups with oncogene induced replication stress, may benefit from inhibition of ATR as therapeutic intervention.
HostingRepository	PRIDE
AnnounceDate	2021-11-02
AnnouncementXML	Submission_2021-11-02_07:00:51.850.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Carina Sihlbom
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2021-07-08 04:20:11	ID requested
⏵ 1	2021-11-02 07:00:52	announced

Dataset with its publication pending

submitter keyword: ATR inhibitor, ALK, neuroblastoma, phosphorylation

Carina Sihlbom
contact affiliation	Proteomics Core Facility, Sahlgrenska Academy, University of Gothenburg
contact email	carina.sihlbom@gu.se
lab head
Carina Sihlbom
contact affiliation	Proteomics Core Facility / University of Gothenburg
contact email	carina.sihlbom@gu.se
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD027187
     1. Label: PRIDE project
     2. Name: ATR inhibition enables complete tumour regression in ALK-driven NB mouse models