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

Anaplastic Lymphoma Kinase (ALK) is a tyrosine kinase receptor which is a clinical target of major interest in cancers. Mutations and rearrangements trigger the activation of this receptor and its downstream signaling pathways. ALK mutations have been identified in both familial and sporadic neuroblastoma (NB) cases and have also been reported in 30-40% of relapsed NB cases, which makes ALK a bonafide target in the therapy for neuroblastoma. ALK tyrosine kinase inhibitors (TKIs) are currently in clinical use for the treatment of ALK-positive non-small cell lung cancer (NSCLC) patients. However, monotherapy with the ALK inhibitor crizotinib did not result in important responses in neuroblastoma patients with ALK alterations, raising the question if combinatory therapy would be more effective. In this study we established both phospho-proteomic and gene expression profiles of ALK activity in neuroblastoma cells employing 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 a number of important leads for novel combinatorial treatment strategies for neuroblastoma patients as well as an increased understanding of ALK signaling involved in this disease.