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Sci Signal. 2018 Nov 20;11(557). pii: eaar5680. doi: 10.1126/scisignal.aar5680.

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

Author information

1
Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Göteborg, Sweden.
2
Department of Human Structure and Repair, Anatomy and Embryology Unit, Ghent University, 9000 Ghent, Belgium.
3
Institution for Molecular Biology, Umeå University, SE-901 87 Umeå, Sweden.
4
Department of Oncogenomics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, Netherlands.
5
Children's Hospital affiliated with Zhengzhou University, 450018 Zhengzhou, China.
6
Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Göteborg, Sweden. bengt.hallberg@gu.se ruth.palmer@gu.se.

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.

PMID:
30459281
DOI:
10.1126/scisignal.aar5680

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