Cancer therapy frequently fails due to the emergence of resistance. Many tumors include phenotypically immature tumor cells, which have been implicated in therapy resistance. Neuroblastoma cells can adopt a lineage-committed adrenergic (ADRN) or an immature mesenchymal (MES) state. They differ in epigenetic landscape and transcription factors, and MES cells are more resistant to chemotherapy. Here we analyzed the response of MES cells to targeted drugs. Activating anaplastic lymphoma kinase ( ALK ) mutations are frequently found in neuroblastoma and ALK inhibitors (ALKi) are in clinical trials. ALKi treatment of ADRN neuroblastoma cells with a tumor-driving ALK mutation induced cell death. Conversely, MES cells did not express either mutant or wild-type ALK and were resistant to ALKi, and MES cells formed tumors that progressed under ALKi therapy. In assessing the role of MES cells in relapse development, TRAIL was identified to specifically induce apoptosis in MES cells and to suppress MES tumor growth. Addition of TRAIL to ALKi treatment of neuroblastoma xenografts delayed relapses in a subset of the animals, suggesting a role for MES cells in relapse formation. While ADRN cells resembled normal embryonal neuroblasts, MES cells resembled immature precursor cells, which also lacked ALK expression. Resistance to targeted drugs can therefore be an intrinsic property of immature cancer cells based on their resemblance to developmental precursors. Significance: In neuroblastoma, mesenchymal tumor cells lack expression of the tumor-driving ALK oncogene and are resistant to ALKi, but dual treatment with ALKi and mesenchymal cell–targeting TRAIL delays tumor relapse.

中文翻译：

---

间充质型神经母细胞瘤细胞逃避 ALK 抑制剂

由于耐药性的出现，癌症治疗经常失败。许多肿瘤包括表型不成熟的肿瘤细胞，这些细胞与治疗抗性有关。神经母细胞瘤细胞可以采用谱系定型肾上腺素 (ADRN) 或未成熟间充质 (MES) 状态。它们在表观遗传景观和转录因子方面有所不同，而且 MES 细胞对化学疗法的抵抗力更强。在这里，我们分析了 MES 细胞对靶向药物的反应。激活间变性淋巴瘤激酶 (ALK) 突变经常在神经母细胞瘤中发现，而 ALK 抑制剂 (ALKi) 正在临床试验中。ALKi 治疗具有肿瘤驱动 ALK 突变的 ADRN 神经母细胞瘤细胞诱导细胞死亡。相反，MES 细胞不表达突变型或野生型 ALK，并且对 ALKi 具有抗性，并且 MES 细胞形成了在 ALKi 治疗下进展的肿瘤。在评估 MES 细胞在复发发展中的作用时，TRAIL 被确定为特异性诱导 MES 细胞凋亡并抑制 MES 肿瘤生长。将 TRAIL 添加到神经母细胞瘤异种移植物的 ALKi 治疗延迟了一部分动物的复发，表明 MES 细胞在复发形成中的作用。虽然 ADRN 细胞类似于正常的胚胎成神经细胞，但 MES 细胞类似于未成熟的前体细胞，它们也缺乏 ALK 表达。因此，基于与发育前体的相似性，对靶向药物的抗性可能是未成熟癌细胞的固有特性。意义：在神经母细胞瘤中，间充质肿瘤细胞缺乏驱动肿瘤的 ALK 致癌基因的表达并且对 ALKi 具有抗性，但使用 ALKi 和间充质细胞靶向 TRAIL 的双重治疗可延缓肿瘤复发。