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Integrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma

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Sci. Signal.  20 Nov 2018:
Vol. 11, Issue 557, eaap9752
DOI: 10.1126/scisignal.aap9752

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Alternatives to ALK in neuroblastoma

Neuroblastoma is a common pediatric solid tumor that is often driven by oncogenic mutations or rearrangements of the gene encoding the tyrosine kinase receptor ALK. In relapsed neuroblastoma, the frequency of ALK mutation is increased, highlighting the importance of understanding ALK signaling in this cancer. Two papers identify alternative targets in ALK-driven neuroblastoma cells. By combining various proteomics analyses with protein-protein interaction networks, Emdal et al. found that IRS2, an adaptor protein in the insulin receptor signaling pathway, linked ALK signaling to neuroblastoma cell survival. Van den Eynden et al. integrated proteomics and gene expression analyses to identify ETS family transcription factors and the MAPK phosphatase DUSP4 as targets of ALK signaling. These papers identify new targets that could be exploited to treat ALK-positive neuroblastoma.

Abstract

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 proteome. We identified the signaling adaptor protein IRS2 (insulin receptor substrate 2) as a major ALK target and an ALK TKI–sensitive signaling node in neuroblastoma cells driven by oncogenic ALK. TKI treatment decreased the recruitment of IRS2 to ALK and reduced the tyrosine phosphorylation of IRS2. Furthermore, siRNA-mediated depletion of ALK or IRS2 decreased the phosphorylation of the survival-promoting kinase Akt and of a downstream target, the transcription factor FoxO3, and reduced the viability of three ALK-driven neuroblastoma cell lines. Collectively, our IPP analysis provides insight into the proximal architecture of oncogenic ALK signaling by revealing IRS2 as an adaptor protein that links ALK to neuroblastoma cell survival through the Akt-FoxO3 signaling axis.

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