Neuroblastoma (NB) is a predominantly pediatric cancer with greater than 90% of cases arising in children under the age of five. More than half of patients have metastases detected at diagnosis, and high-risk disease is associated with five-year survival rates of only 50–60 %. Standard therapy involves highly toxic chemotherapy, surgery, radiation, and immunotherapy, and less toxic, more specific targeted therapies are urgently needed. Genomic studies have identified common driver aberrations in high-risk NB, such as MYCN amplification. In addition, a proportion of high-risk patients harbor amplification or activating mutations in anaplastic lymphoma kinase (ALK), and co-occurrence of ALK mutations and MYCN amplification have been associated with aggressive disease. In this study, we analyzed the efficacy of a Phase Ia-cleared, orally bioavailable dual ALK and focal adhesion kinase (FAK) inhibitor, ESK440, in multiple preclinical NB models. ESK440 potently inhibited proliferation of NB cell lines, with increased sensitivity in cell lines harboring ALK aberrations. ALK, FAK, and downstream target activation were rapidly decreased upon ESK440 treatment, and this was associated with impaired cellular migration and invasion. Importantly, ESK440 treatment also decreased MYCN levels. NB cell line and patient-derived xenograft studies showed significant reduction in tumor growth in ESK440-treated mice with no signs of toxicity. In certain NB models, ESK440 showed comparable or enhanced efficacy to lorlatinib, another clinical ALK inhibitor, and a lorlatinib-resistant cell line (COG-N-561 LR) retained sensitivity to ESK440. These preclinical results indicate that ESK440 is a promising targeted agent for ALK-driven NB and support future clinical studies to evaluate its efficacy in NB patients.

神经母细胞瘤 (NB) 是一种主要是儿童癌症，超过 90% 的病例发生在五岁以下的儿童中。超过一半的患者在诊断时已检测到转移，而高危疾病的五年生存率仅为 50-60%。标准治疗包括高毒性化疗、手术、放疗和免疫治疗，迫切需要毒性较小、更具特异性的靶向治疗。基因组研究已经确定了高风险 NB 中常见的驱动畸变，例如MYCN扩增。此外，一部分高危患者存在间变性淋巴瘤激酶 ( ALK ) 扩增或激活突变，并且ALK突变和MYCN扩增同时发生与侵袭性疾病相关。在这项研究中，我们分析了 Ia 期已明确的、口服生物可利用的双重 ALK 和粘着斑激酶 (FAK) 抑制剂 ESK440 在多个临床前 NB 模型中的功效。ESK440 有效抑制 NB 细胞系的增殖，并提高含有ALK畸变的细胞系的敏感性。ESK440 治疗后 ALK、FAK 和下游靶点激活迅速减少，这与细胞迁移和侵袭受损有关。重要的是，ESK440 治疗还降低了 MYCN 水平。NB 细胞系和患者来源的异种移植研究表明，ESK440 治疗小鼠的肿瘤生长显着减少，且没有毒性迹象。在某些 NB 模型中，ESK440 显示出与另一种临床 ALK 抑制剂 lorlatinib 相当或增强的功效，并且 lorlatinib 耐药细胞系 (COG-N-561 LR) 保留了对 ESK440 的敏感性。这些临床前结果表明，ESK440 是一种有前途的 ALK 驱动的 NB 靶向药物，并支持未来的临床研究，以评估其在 NB 患者中的疗效。