PXD041824-1

PXD041824 is an original dataset announced via ProteomeXchange.

Title	ALK signalling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition
Description	High-risk neuroblastoma (NB) currently presents significant clinical challenges. MYCN and ALK, which are often involved in high-risk NB, lead to increased replication stress in cancer cells, providing options for therapeutic exploitation. We previously identified an ATR/ALK inhibitor combination as an effective therapeutic approach in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signalling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which monotreatment with ATRi resulted in a robust initial response, but subsequent relapse, in contrast to a 14-day ALKi/ATRi combination treatment that resulted in robust and sustained responses. Finally, we show that the remarkable response to the 14-day combined ATR/ALK inhibition protocol reflects a robust differentiation response in the tumour, reprogramming tumour cells to a neuronal/Schwann cell lineage identity. Our results identify a unique ability of ATR inhibition to trigger neuroblastoma differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.
HostingRepository	PRIDE
AnnounceDate	2023-12-13
AnnouncementXML	Submission_2023-12-13_05:52:36.552.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Evelin Berger
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	methylthiolated residue; phosphorylated residue; monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-26 05:48:31	ID requested
⏵ 1	2023-12-13 05:52:36	announced

Dataset with its publication pending

submitter keyword: ALK, ATR, elimusertib, neuroblastoma, lorlatinib, ALKAL, DDR, ceralasertib

Carina Sihlbom
contact affiliation	Proteomics Core Facility University of Gothenburg Sweden
contact email	carina.sihlbom@gu.se
lab head
Evelin Berger
contact affiliation	University of Gothenburg
contact email	evelin.berger@gu.se
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD041824
     1. Label: PRIDE project
     2. Name: ALK signalling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition