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 inALK-mutated NB cells. Mechanistically, both ALK and IGF1R contribute significantly to the activation of downstream PI3K-AKT and RAS-MAPK signaling pathways inALK-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 inALK-mutated NB and that co-targeting of ALK and IGF1R may be advantageous in clinical treatment ofALK-mutated NB patients.
间变性淋巴瘤激酶（ALK）通过激活点突变或扩增导致的异常活化，驱动了5-12%的神经母细胞瘤（NB）的发生。先前的研究已证实胰岛素样生长因子1受体（IGF1R）这一受体酪氨酸激酶（RTK）在多种癌症中发挥作用。本研究显示，许多NB细胞系表现出IGF1R活性，且在ALK驱动的NB细胞中，抑制IGF1R会导致细胞增殖不同程度地下降。此外，联合抑制ALK和IGF1R能产生协同抗增殖效应，尤其是在ALK突变的NB细胞中。从机制上看，在ALK突变的NB细胞中，ALK和IGF1R均显著促进下游PI3K-AKT和RAS-MAPK信号通路的激活。然而，这两种RTK利用不同的衔接蛋白组合来介导下游信号效应。本研究发现，ALK信号通过优先磷酸化衔接蛋白GAB1、GAB2和FRS2来激活RAS-MAPK通路，而IGF1R信号则优先磷酸化IRS2，从而促进PI3K-AKT通路的激活。综上所述，这些发现揭示了IGF1R RTK在ALK突变NB中潜在的重要作用，并表明在ALK突变NB患者的临床治疗中，同时靶向ALK和IGF1R可能具有优势。
肿瘤(癌症)患者之家