-
摘要: 神经母细胞瘤(neuoblastonma, NB)是小儿最常见的实体肿瘤之一, 临床表现变异较大, 高危NB进展迅速, 即使行高强度清髓化疗, 肿瘤复发仍然常见, 死亡率较高为发现有效NB治疗药物和靶点, 必须充分研究认识NB发病机制中的关键分子。间变性淋巴瘤激酶(ALK)是一种受体型酪氨酸激酶, 其异常存在于多种肿瘤中, 与肿瘤发生发展密切相关, 如间变性大细胞淋巴瘤、横纹肌肉瘤、炎症性肌纤维母细胞瘤、NB。ALK的异常形式主要包括基因融合、基因突变、基因扩增及蛋白表达增加随着酪氨酸激酶抑制剂在临床抗肿瘤治疗中的应用以及新的特异性小分子ALK抑制剂的研发, ALK异常与NB发生发展关系及针对ALK异常的NB靶向治疗获得了较多关注和研究。本文主要针对ALK异常与NB发生发展关系的研究进行综述。Abstract: Neuroblastoma(NB), one of the most common solid tumors in children, has widely varied clinical manifestations. High-risk NB progresses rapidly; even with intensive myeloablative chemotherapy, relapse is still common and almost all are fatal.To discover effective drugs and improve the prognosis of NB, the critical molecules in the pathogenesis of NB need to be examined. Anaplastic lymphoma kinase(ALK) is a member of the insulin receptor superfamily of receptor tyrosine kinases.ALK abnormalities exist in a variety of tumors, such as anaplastic large cell lymphoma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, and NB. The abnormal forms of ALK include gene fusion, gene amplification, protein overexpression, and gene mutation.These abnormalities play important roles in the development of these tumors.Tyrosine kinase inhibitors as anti-cancer therapy for clinical applications and new specific small-molecule inhibitors of ALK have been developed.Consequently, the relationships of ALK aberrations with NB development and targeted ALK treatments for NB have received increased attention.This article mainly reviews the studies on the relationship between ALK abnormalities and NB development.
-
Key words:
- Neuroblastoma /
- Anaplastic lymphoma kinase /
- Genetic abnormality /
- Targeted therapy
-
[1] Schor NF. New approaches to pharmacotherapy of rumors of the nervous system during childhood and adolescence[J]. Pharmacol Ther, 2009, 122(1): 44-55. doi: 10.1016/j.pharmthera.2009.01.001 [2] Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group[J]. N Engl J Med, 1999, 341(16): 1165-1173. doi: 10.1056/NEJM199910143411601 [3] Li R, Morris SW. Development of anaplastic lymphoma kinase (ALK) small—molecule inhibitors for cancer therapy[J]. Med Res Rev, 2008, 28(3): 372-412. doi: 10.1002/med.20109 [4] Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non—Hodgkin's lymphoma[J]. Science, 1994, 263(5151): 1281-1284. doi: 10.1126/science.8122112 [5] Chiarle R, Voena C, Ambrogio C, et al. The anaplastic lymphoma kinase in the pathogenesis of cancer[J]. Nat Rev Cancer, 2008, 8(1): 11-23. [6] Pearson R, Kolesar JM. Targeted therapy for NSCLC: ALK inhibition[J]. J Oncol Pharm Pract, 2011, [Epub ahead of print]. [7] Chen Y, Takita J, Choi YL, et al. Oncogenic mutations of ALK kinase in neuroblastoma[J]. Nature, 2008, 455(7215): 971-974. doi: 10.1038/nature07399 [8] Murugan AK, Xing M. Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene[J]. Cancer Res, 2011, 71(13): 4403-4411. [9] Osajima -Hakomori Y, Miyake I, Ohira M, et al. Biological role of anaplastic lymphoma kinase in neuroblastoma[J]. Am J Pathol, 2005, 167(1): 213-222. [10] Salido M, Pijuan L, Martinez—Aviles L, et al. Increased ALK gene copy number and amplification are frequent in non—small cell lung cancer[J]. J Thorac Oncol, 2011, 6(1): 21-27. doi: 10.1097/JTO.0b013e3181fb7cd6 [11] Corao DA, Biegel JA, Coffin CM, et al. ALK expression in rhabdomyosarcomas: correlation with histologic subtype and fusion status[J]. Pediatr Dev Pathol, 2009, 12(4): 275-283. doi: 10.2350/08-03-0434.1 [12] Perez Pinera P, Chang Y, Astudillo A, et al. Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer[J]. Biochem Biophys Res Commun, 2007, 358(2): 399-403. doi: 10.1016/j.bbrc.2007.04.137 [13] Lamant L, Pulford K, Bischof D, et al. Expression of the ALK tyrosine kinase gene in neuroblastoma[J]. Am J Pathol, 2000, 156(5): 1711-1721. doi: 10.1016/S0002-9440(10)65042-0 [14] George RE, Sanda T, Hanna M, et al. Activating mutations in ALK provide a therapeutic target in neuroblastom[J]. Nature. 2008, 455 (7215): 975-978. [15] Miyake I, Hakomori Y, Shinohara A, et al. Activation of anaplastic lymphoma kinase is responsible for hyper-phosphorylation of ShcC in neuroblastoma cell lines[J]. Oncogene, 2002, 21(138): 5823-5834. http://www.onacademic.com/detail/journal_1000034776288810_001d.html [16] De Brouwer S, De Preter K, Kumps C, et al. Meta-analysis of Neuroblastomas Reveals a Skewed ALK Mutation Spectrum in Tumors with MYCN Amplification[J]. Clin Cancer Res, 2010, 16(17): 4353-4362. doi: 10.1158/1078-0432.CCR-09-2660 [17] Caren H, Abel F, Kogner P, et al. High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumors[J]. Biochem J, 2008, 416(2): 153-159. doi: 10.1042/BJ20081834 [18] Mosse YP, Laudenslager M, Longo L, et al. Identification of ALK as a major familial neuroblastoma predisposition gene[J]. Nature, 2008, 455(7215): 930-935. doi: 10.1038/nature07261 [19] Duijkers FA, Gaal J, Meijerink JP, et al. Anaplastic lymphoma kinase (ALK) inhibitor response in neuroblastoma is highly correlat- ed with ALK mutation status, ALK mRNA and protein levels[J]. Cell Oncol(Dordr), 2011, 34(5): 409-417. doi: 10.1007/s13402-011-0048-2 [20] McDermott U, lafrate AJ, Gray NS, et al. Genomic Alterations of Anaplastic Lymphoma Kinase May Sensitize Tumors to Anaplastic Lymphoma Kinase Inhibitors[J]. Cancer Res, 2008, 68(9): 3389-3395. doi: 10.1158/0008-5472.CAN-07-6186 [21] Janoueix—Lerosey I, Lequin D, Brugieres L, et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma[J]. Nature, 2008, 455(7215): 967-970. doi: 10.1038/nature07398 [22] Schönherr C, Ruuth K, Eriksson T, et al. The Neuroblastoma ALK(I1250T) Mutation Is a Kinase-Dead RTK In Vitro and In Vivo[J]. Translational Oncology, 2011, 4(4): 258-265. [23] Martinsson T, Eriksson T. Abrahamsson J, et al. Appearance of the novel activating F1174S ALK mutation in neuroblastoma correlates with aggressive tumor progression and unresponsiveness to therapy[J]. Cancer Res, 2011, 71(1): 98-105. doi: 10.1158/0008-5472.CAN-10-2366 [24] Sch(o|¨)nherr C, Ruuth K, Yamazaki Y, et al. Activating ALK mutations found in neuroblastoma are inhibited by Crizotinib and NVP-TAE684[J]. Biochem J, 2011, 440(3): 405-413. doi: 10.1042/BJ20101796 [25] Passoni L, Longo L, Collini P. et al. Mutation—independent anaplastic lymphoma kinase overexpression in poor prognosis neuroblastoma patients[J]. Cancer Res, 2009, 69(18): 7338-7346. doi: 10.1158/0008-5472.CAN-08-4419 [26] SchulteJH, Bachmann HS, Brockmeyer B, et al. High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma[J]. Clin Cancer Re, 2011, 17(15): 5082-5092. doi: 10.1158/1078-0432.CCR-10-2809
点击查看大图
计量
- 文章访问数: 45
- HTML全文浏览量: 2
- PDF下载量: 0
- 被引次数: 0