激活点突变或扩增引发的异常活化持续震荡淋巴瘤激酶（ALK）在神经母细胞瘤（NB）中占5-12％。以往的研究已经发现，在多种癌症中参与了胰岛素样生长因子1受体（IGF1R）受体酪氨酸激酶（RTK）。我们在这里展示了许多NB细胞系表现出IGF1R活性，并且IGF1R抑制导致了ALK驱动的NB细胞的细胞增殖的不同程度的减少。此外，ALK和IGF1R的联合抑制导致协同的抗增殖效应，尤其是在ALK突变的NB细胞中。在ALK突变的NB细胞中，ALK和IGF1R两者在启动下游PI3K-AKT和RAS-MAPK信号通路方面发挥了重要作用。然而，这两种RTK利用不同的适配蛋白库实现下游信号效应的介导。我们在这里展示了ALK信号通过优先磷酸化适配蛋白GAB1、GAB2和FRS2而导致RAS-MAPK途径的活化，而IGF1R信号则优先磷酸化IRS2，促进PI3K-AKT途径的活化。总之，这些发现揭示了IGF1R RTK在ALK突变的NB中可能发挥重要作用，并且在ALK突变的NB患者的临床治疗中共同靶向ALK和IGF1R可能是有利的。

Aberrant activation of anaplastic lymphoma kinase (ALK) by activating point mutation or amplification drives 5-12% of neuroblastoma (NB). Previous work has identified the involvement of the insulin-like growth factor 1 receptor (IGF1R) receptor tyrosine kinase (RTK) in a wide range of cancers. We show here that many NB cell lines exhibit IGF1R activity, and that IGF1R inhibition led to decreased cell proliferation to varying degrees in ALK-driven NB cells. Furthermore, combined inhibition of ALK and IGF1R resulted in synergistic anti-proliferation effects, in particular in ALK-mutated NB cells. Mechanistically, both ALK and IGF1R contribute significantly to the activation of downstream PI3K-AKT and RAS-MAPK signaling pathways in ALK-mutated NB cells. However, these two RTKs employ a differential repertoire of adaptor proteins to mediate downstream signaling effects. We show here that ALK signaling led to activation of the RAS-MAPK pathway by preferentially phosphorylating the adaptor proteins GAB1, GAB2, and FRS2, while IGF1R signaling preferentially phosphorylated IRS2, promoting activation of the PI3K-AKT pathway. Together, these findings reveal a potentially important role of the IGF1R RTK in ALK-mutated NB and that co-targeting of ALK and IGF1R may be advantageous in clinical treatment of ALK-mutated NB patients.