biostudies-literatureEmdal KBNovo Nordisk FoundationEuropean Union’s 7th Framework ProgrammeNational Institute for Health Research (NIHR)Novo Nordisk Foundation Center for Protein ResearchEMBO long-term fellowshipDanish Cancer SocietyLundbeckfondenWellcome TrustLundbeck FoundationEuropean Union’s Horizon 2020 research and innovation programmeWellcome Trust Sir Henry Dale fellowshipeaap9752https://www.ebi.ac.uk/biostudies/studies/S-EPMC7618099biostudies-literatureUnknown11(557)Oncogenic anaplastic lymphoma kinase (ALK) is one of the few druggable targets in neuroblastoma, and therapy resistance to ALK-targeting tyrosine kinase inhibitors (TKIs) comprises an inevitable clinical challenge. Therefore, a better understanding of the oncogenic signaling network rewiring driven by ALK is necessary to improve and guide future therapies. Here, we performed quantitative mass spectrometry-based proteomics on neuroblastoma cells treated with one of three clinically relevant ALK TKIs (crizotinib, LDK378, or lorlatinib) or an experimentally used ALK TKI (TAE684) to unravel aberrant ALK signaling pathways. Our integrated proximal proteomics (IPP) strategy included multiple signaling layers, such as the ALK interactome, phosphotyrosine interactome, phosphoproteome, and proteomeScience signalingIntegrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma.PMC7618099686547R90-A5844259348-ASSETNNF14CC00018107636/Z/15/ZALTF 746-2009107636IS-BRC-1215-20005R193-2015-243R191-2015-703PI Jesper Velgaard OlsenLundby ASpeleman FOlsen JVPedersen AKEmdal KBFrancavilla CClaeys SBekker-Jensen DBDe Preter KfalseIntegrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma.Oncogenic anaplastic lymphoma kinase (ALK) is one of the few druggable targets in neuroblastoma, and therapy resistance to ALK-targeting tyrosine kinase inhibitors (TKIs) comprises an inevitable clinical challenge. Therefore, a better understanding of the oncogenic signaling network rewiring driven by ALK is necessary to improve and guide future therapies. Here, we performed quantitative mass spectrometry-based proteomics on neuroblastoma cells treated with one of three clinically relevant ALK TKIs (crizotinib, LDK378, or lorlatinib) or an experimentally used ALK TKI (TAE684) to unravel aberrant ALK signaling pathways. Our integrated proximal proteomics (IPP) strategy included multiple signaling layers, such as the ALK interactome, phosphotyrosine interactome, phosphoproteome, and proteome2018-01-01T00:00:00Z2018 Nov2026-06-02T20:26:40.222Z2026-04-20T03:10:13.57ZS-EPMC76180993045928310.1126/scisignal.aap9752