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.

间变性淋巴瘤激酶（ALK）是酪氨酸激酶受体，是对癌症最感兴趣的临床靶标。ALK中的突变和重排触发了编码受体及其下游信号通路的激活。在家族性和散发性神经母细胞瘤病例中以及在30％至40％的复发中都发现了ALK突变，这使ALK成为神经母细胞瘤治疗的真正靶点。针对ALK的酪氨酸激酶抑制剂（TKIs）目前正在临床上用于治疗ALK阳性的非小细胞肺癌患者。但是，ALK抑制剂克唑替尼的单药治疗在神经母细胞瘤ALK患者中不太令人鼓舞改变，提出了组合疗法是否会更有效的问题。在这项研究中，我们建立了暴露于第一代和第三代ALK TKI的神经母细胞瘤细胞中ALK活性的磷酸化蛋白质组学和基因表达谱，以鉴定潜在的分子机制并鉴定相关的生物标志物，信号网络和新的治疗靶标。该分析为神经母细胞瘤患者提供了新颖的组合治疗策略的各种重要线索，并加深了对该疾病涉及的ALK信号的理解。