Division of Pediatric Hematology-Oncology, Children's Hospital of the King's Daughters, Norfolk, VA, USA.
Paediatr Drugs. 2013 Jun;15(3):163-9. doi: 10.1007/s40272-013-0027-3.
Anaplastic lymphoma kinase (ALK) is an oncogenic tyrosine kinase that is deregulated due to a variety of molecular mechanisms in pediatric cancer. They include chromosomal translocations, activation mutations, and gene amplifications. Since the initial discovery of ALK as an oncogenic tyrosine kinase involved in the chromosomal translocation t(2, 5)(p23;q35) in 1994, more than 20 translocation partners of ALK have been identified in various cancers. Furthermore, deregulation of ALK tyrosine kinase activity is critical for the pathogenesis of several other pediatric tumors, including neuroblastomas and inflammatory myofibroblastic tumors. The recent discovery of ALK translocations in adult lung cancer patients (non-small cell lung cancer) has accelerated the development of inhibitors of ALK tyrosine kinase as therapeutic agents. While excellent clinical response has been observed in many patients, the acquisition of clinical resistance to ALK inhibition highlights the need for development of second-generation ALK kinase inhibitors and/or combination therapies that target downstream signaling mediators or antibody drug conjugates. This article provides an update on the spectrum of ALK-driven tumors in the pediatric population and the potential therapies which target these tumors.
间变性淋巴瘤激酶（ALK）是一种致癌酪氨酸激酶，由于儿科癌症中多种分子机制的失调而被激活。这些机制包括染色体易位、激活突变和基因扩增。自 1994 年首次发现 ALK 作为一种参与染色体易位 t（2,5）（p23；q35）的致癌酪氨酸激酶以来，已经在各种癌症中鉴定出超过 20 种 ALK 的易位伙伴。此外，ALK 酪氨酸激酶活性的失调对于包括神经母细胞瘤和炎症性肌纤维母细胞瘤在内的几种其他儿科肿瘤的发病机制至关重要。最近在成年肺癌患者（非小细胞肺癌）中发现 ALK 易位加速了 ALK 酪氨酸激酶抑制剂作为治疗剂的开发。虽然许多患者观察到了极好的临床反应，但对 ALK 抑制的临床耐药性的获得突出表明需要开发第二代 ALK 激酶抑制剂和/或靶向下游信号转导介质的联合治疗或抗体药物偶联物。本文提供了儿科人群中由 ALK 驱动的肿瘤的最新情况以及针对这些肿瘤的潜在治疗方法。
