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Anaplastic lymphoma kinase

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Title: Anaplastic lymphoma kinase  
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Anaplastic lymphoma kinase

Anaplastic lymphoma receptor tyrosine kinase

Human anaplastic lymphoma kinase in complex with crizotinib. PDB [1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; CD246; NBLST3
External IDs ChEMBL: GeneCards:
EC number
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ALK gene.[2][3]

Function

ALK plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system.[3]

The deduced amino acid sequences reveal that ALK is a novel receptor tyrosine kinase having a putative transmembrane domain and an extracellular domain. These sequences are absent in the product of the transforming NPM-ALK gene.[4] ALK shows the greatest sequence similarity to LTK (leukocyte tyrosine kinase).

Pathology

The ALK gene can be oncogenic in three ways – by forming a fusion gene with any of several other genes, by gaining additional gene copies or with mutations of the actual DNA code for the gene itself.

Anaplastic large-cell lymphoma

The 2;5 chromosomal translocation is associated with approximately 60% anaplastic large-cell lymphomas (ALCLs). The translocation creates a fusion gene consisting of the ALK (anaplastic lymphoma kinase) gene and the nucleophosmin (NPM) gene: the 3' half of ALK, derived from chromosome 2 and coding for the catalytic domain, is fused to the 5' portion of NPM from chromosome 5. The product of the NPM-ALK fusion gene is oncogenic. In a smaller fraction of ALCL patients, the 3' half of ALK is fused to the 5' sequence of TPM3 gene, encoding for tropomyosin 3. In rare cases, ALK is fused to other 5' fusion partners, such as TFG, ATIC, CLTC1, TPM4, MSN, ALO17, MYH9.[5]

Adenocarcinoma of the lung

The EML4-ALK fusion gene is responsible for approximately 3-5% of non-small-cell lung cancer(NSCLC). The vast majority of cases are adenocarcinomas. The standard test used to detect this gene in tumor samples is fluorescence in situ hybridization (FISH) by a US FDA approved kit. Recently Roche Ventana has got the approval of Chinese FDA and European FDA to test mutation by IHC. Other techniques like reverse-transcriptase PCR (RT-PCR) can also be used to detect lung cancers with an ALK gene fusion but not recommended. ALK lung cancers are found in patients of all ages, although on average these patients may be somewhat younger. ALK lung cancers are more common in light cigarette smokers or nonsmokers, but a significant number of patients with this disease are current or former cigarette smokers. EML4-ALK-rearrangement in NSCLC is exclusive and not found in EGFR- or KRAS-mutated tumors[6]

Gene rearrangements and overexpression in other tumours

ALK inhibitors

Xalkori (crizotinib), produced by Pfizer, was approved by the FDA for treatment of late stage lung cancer on August 26, 2011.[21] Early results of an initial Phase I trial with 82 patients with ALK induced lung cancer showed an overall response rate of 57%, a disease control rate at 8 weeks of 87% and progression free survival at 6 months of 72%.

See also

References

  1. ^ Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I, McTigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, Yamazaki S, Li Q, Zou H, Christensen J, Mroczkowski B, Bender S, Kania RS, Edwards MP (September 2011). "Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)". J. Med. Chem. 54 (18): 6342–63.  
  2. ^ Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT (Apr 1994). "Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma". Science 263 (5151): 1281–4.  
  3. ^ a b "Entrez Gene: ALK anaplastic lymphoma kinase (Ki-1)". 
  4. ^ Iwahara, T; Fujimoto, J; Wen, D; Cupples, R; Bucay, N; Arakawa, T; Mori, S; Ratzkin, B; Yamamoto, T (Jan 30, 1997). "Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system". Oncogene 14 (4): 439–49.  
  5. ^ Mologni L (July 2012). "Inhibitors of the anaplastic lymphoma kinase". Expert Opin Investig Drugs 21 (7): 985–94.  
  6. ^ Travis WD, Brambilla E, Noguchi M, et al.: IASLC/ATS/ERS international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011; 6: 244–85
  7. ^ Mossé YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport E, Devoto M, Maris JM (October 2008). "Identification of ALK as a major familial neuroblastoma predisposition gene". Nature 455 (7215): 930–5.  
  8. ^ Cools J, Wlodarska I, Somers R, Mentens N, Pedeutour F, Maes B, De Wolf-Peeters C, Pauwels P, Hagemeijer A, Marynen P (August 2002). "Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor". Genes Chromosomes Cancer 34 (4): 354–62.  
  9. ^ Lawrence B, Perez-Atayde A, Hibbard MK, Rubin BP, Dal Cin P, Pinkus JL, Pinkus GS, Xiao S, Yi ES, Fletcher CD, Fletcher JA (August 2000). "TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors". Am. J. Pathol. 157 (2): 377–84.  
  10. ^ Sukov WR, Hodge JC, Lohse CM, Akre MK, Leibovich BC, Thompson RH, Cheville JC (November 2012). "ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients". Mod. Pathol. 25 (11): 1516–25.  
  11. ^ Sugawara E, Togashi Y, Kuroda N, Sakata S, Hatano S, Asaka R, Yuasa T, Yonese J, Kitagawa M, Mano H, Ishikawa Y, Takeuchi K (September 2012). "Identification of anaplastic lymphoma kinase fusions in renal cancer: large-scale immunohistochemical screening by the intercalated antibody-enhanced polymer method". Cancer 118 (18): 4427–36.  
  12. ^ Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, Nelson M, Bridge JA (March 2011). "Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum". Mod. Pathol. 24 (3): 430–42.  
  13. ^ Mariño-Enríquez A, Ou WB, Weldon CB, Fletcher JA, Pérez-Atayde AR (March 2011). "ALK rearrangement in sickle cell trait-associated renal medullary carcinoma". Genes Chromosomes Cancer 50 (3): 146–53.  
  14. ^ Jazii FR, Najafi Z, Malekzadeh R, Conrads TP, Ziaee AA, Abnet C, Yazdznbod M, Karkhane AA, Salekdeh GH (November 2006). "Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer". World J. Gastroenterol. 12 (44): 7104–12.  
  15. ^ Yaakup H, Sagap I, Fadilah SA (October 2008). "Primary oesophageal Ki (CD30)-positive ALK+ anaplastic large cell lymphoma of T-cell phenotype". Singapore Med J 49 (10): e289–92.  
  16. ^ a b Lin E, Li L, Guan Y, Soriano R, Rivers CS, Mohan S, Pandita A, Tang J, Modrusan Z (September 2009). "Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers". Mol. Cancer Res. 7 (9): 1466–76.  
  17. ^ Tuma RS (January 2012). "ALK gene amplified in most inflammatory breast cancers". J. Natl. Cancer Inst. 104 (2): 87–8.  
  18. ^ Powers C, Aigner A, Stoica GE, McDonnell K, Wellstein A (April 2002). "Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth". J. Biol. Chem. 277 (16): 14153–8.  
  19. ^ Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C, Caughey DJ, Wen D, Karavanov A, Riegel AT, Wellstein A (May 2001). "Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin". J. Biol. Chem. 276 (20): 16772–9.  
  20. ^ Murugan AK, Xing M (July 2011). "Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene". Cancer Res. 71 (13): 4403–11.  
  21. ^ "Xalkori Approved for Lung Cancer". FDA. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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