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Phosphoproteome and gene expression profiling of ALK inhibition in neuroblastoma cell lines reveals conserved oncogenic pathways

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Sci. Signal.  20 Nov 2018:
Vol. 11, Issue 557, eaar5680
DOI: 10.1126/scisignal.aar5680

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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

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is a clinical target of major interest in cancer. Mutations and rearrangements in ALK trigger the activation of the encoded receptor and its downstream signaling pathways. ALK mutations have been identified in both familial and sporadic neuroblastoma cases as well as in 30 to 40% of relapses, which makes ALK a bona fide target in neuroblastoma therapy. Tyrosine kinase inhibitors (TKIs) that target ALK are currently in clinical use for the treatment of patients with ALK-positive non–small cell lung cancer. However, monotherapy with the ALK inhibitor crizotinib has been less encouraging in neuroblastoma patients with ALK alterations, raising the question of whether combinatorial therapy would be more effective. In this study, we established both phosphoproteomic and gene expression profiles of ALK activity in neuroblastoma cells exposed to first- and third-generation ALK TKIs, to identify the underlying molecular mechanisms and identify relevant biomarkers, signaling networks, and new therapeutic targets. This analysis has unveiled various important leads for novel combinatorial treatment strategies for patients with neuroblastoma and an increased understanding of ALK signaling involved in this disease.

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