Data_Sheet_1_Alectinib, an Anaplastic Lymphoma Kinase Inhibitor, Abolishes ALK Activity and Growth in ALK-Positive Neuroblastoma Cells.docx

Oncogenic receptor tyrosine kinases including anaplastic lymphoma kinase (ALK) are implicated in numerous solid and hematologic cancers. ALK mutations are reported in an estimated 9% of neuroblastoma and recent reports indicate that the percentage of ALK-positive cases increases in the relapsed patient population. Initial clinical trial results have shown that it is difficult to inhibit growth of ALK positive neuroblastoma with crizotinib, motivating investigation of next generation ALK inhibitors with higher affinity for ALK. Here, alectinib, a potent next generation ALK inhibitor with antitumor activity was investigated in ALK-driven neuroblastoma models. Employing neuroblastoma cell lines and mouse xenografts we show a clear and efficient inhibition of ALK activity by alectinib. Inhibition of ALK activity was observed in vitro employing a set of different constitutively active ALK variants in biochemical assays. The results suggest that alectinib is an effective inhibitor of ALK kinase activity in ALK addicted neuroblastoma and should be considered as a potential future therapeutic option for ALK-positive neuroblastoma patients alone or in combination with other treatments.

包括间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）在内的致癌性受体酪氨酸激酶，与多种实体瘤及血液系统恶性肿瘤的发生发展密切相关。据报道，约9%的神经母细胞瘤患者携带ALK突变；近期研究显示，复发患者群体中ALK阳性病例的占比有所升高。早期临床试验结果表明，使用克唑替尼（crizotinib）难以抑制ALK阳性神经母细胞瘤的生长，这推动了对ALK亲和力更高的新一代ALK抑制剂的研发。本研究针对ALK驱动型神经母细胞瘤模型，评估了阿来替尼（alectinib）——一种具备抗肿瘤活性的强效新一代ALK抑制剂——的作用效果。通过神经母细胞瘤细胞系与小鼠异种移植模型（mouse xenografts），本研究证实阿来替尼可清晰且高效地抑制ALK的活性。在体外生化实验中，针对一系列不同组成型激活的ALK突变体，同样观测到ALK活性被抑制的现象。研究结果表明，阿来替尼可有效抑制ALK成瘾型神经母细胞瘤的ALK激酶活性，有望作为ALK阳性神经母细胞瘤患者的潜在未来治疗方案，可单独使用或与其他疗法联合应用。