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 ALKgene.[1][2]
ALK plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system.[2]
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.[3] 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.[4]
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 obtained approval in China and European Union countries to test this mutation by immunohistochemistry.[citation needed] Other techniques like reverse-transcriptase PCR (RT-PCR) can also be used to detect lung cancers with an ALK gene fusion but not recommended.[citation needed] ALK lung cancers are found in patients of all ages, although on average these patients tend to be 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.[5]
Gene rearrangements and overexpression in other tumours
Xalkori (crizotinib), produced by Pfizer, was approved by the FDA for treatment of late stage lung cancer on August 26, 2011.[20] 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%.
Ceritinib was approved by the FDA in April 2014 for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.[21]
Entrectinib (RXDX-101) is a selective tyrosine kinase inhibitor developed by Ignyta, Inc., with specificity, at low nanomolar concentrations, for all of three Trk proteins (encoded by the three NTRK genes, respectively) as well as the ROS1, and ALK receptor tyrosine kinases. An open label, multicenter, global phase 2 clinical trial called STARTRK-2 is currently underway to test the drug in patients with ROS1/NTRK/ALK gene rearrangements.
↑Sukov WR, Hodge JC, Lohse CM, Akre MK, Leibovich BC, Thompson RH, Cheville JC (Nov 2012). "ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients". Modern Pathology. 25 (11): 1516–25. doi:10.1038/modpathol.2012.107. PMID22743654.
↑Sugawara E, Togashi Y, Kuroda N, Sakata S, Hatano S, Asaka R, Yuasa T, Yonese J, Kitagawa M, Mano H, Ishikawa Y, Takeuchi K (Sep 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. doi:10.1002/cncr.27391. PMID22252991.
↑Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, Nelson M, Bridge JA (Mar 2011). "Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum". Modern Pathology. 24 (3): 430–42. doi:10.1038/modpathol.2010.213. PMID21076462.
↑Mariño-Enríquez A, Ou WB, Weldon CB, Fletcher JA, Pérez-Atayde AR (Mar 2011). "ALK rearrangement in sickle cell trait-associated renal medullary carcinoma". Genes, Chromosomes & Cancer. 50 (3): 146–53. doi:10.1002/gcc.20839. PMID21213368.
↑Jazii FR, Najafi Z, Malekzadeh R, Conrads TP, Ziaee AA, Abnet C, Yazdznbod M, Karkhane AA, Salekdeh GH (Nov 2006). "Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer". World Journal of Gastroenterology. 12 (44): 7104–12. doi:10.3748/wjg.v12.i44.7104. PMID17131471.
↑Yaakup H, Sagap I, Fadilah SA (Oct 2008). "Primary oesophageal Ki (CD30)-positive ALK+ anaplastic large cell lymphoma of T-cell phenotype". Singapore Medical Journal. 49 (10): e289–92. PMID18946602.
↑ 15.015.1Lin E, Li L, Guan Y, Soriano R, Rivers CS, Mohan S, Pandita A, Tang J, Modrusan Z (Sep 2009). "Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers". Molecular Cancer Research. 7 (9): 1466–76. doi:10.1158/1541-7786.MCR-08-0522. PMID19737969.
↑Tuma RS (Jan 2012). "ALK gene amplified in most inflammatory breast cancers". Journal of the National Cancer Institute. 104 (2): 87–8. doi:10.1093/jnci/djr553. PMID22215853.
↑Powers C, Aigner A, Stoica GE, McDonnell K, Wellstein A (Apr 2002). "Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth". The Journal of Biological Chemistry. 277 (16): 14153–8. doi:10.1074/jbc.M112354200. PMID11809760.
↑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". The Journal of Biological Chemistry. 276 (20): 16772–9. doi:10.1074/jbc.M010660200. PMID11278720.
Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ, Haralambieva E, Pulford K, Pileri S, Morris SW, Mason DY, Delsol G (Mar 1998). "ALK-positive lymphoma: a single disease with a broad spectrum of morphology". Blood. 91 (6): 2076–84. PMID9490693.
Pulford K, Lamant L, Espinos E, Jiang Q, Xue L, Turturro F, Delsol G, Morris SW (Dec 2004). "The emerging normal and disease-related roles of anaplastic lymphoma kinase". Cellular and Molecular Life Sciences. 61 (23): 2939–53. doi:10.1007/s00018-004-4275-9. PMID15583856.
Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T (Jan 1997). "Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system". Oncogene. 14 (4): 439–49. doi:10.1038/sj.onc.1200849. PMID9053841.
Morris SW, Naeve C, Mathew P, James PL, Kirstein MN, Cui X, Witte DP (May 1997). "ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK)". Oncogene. 14 (18): 2175–88. doi:10.1038/sj.onc.1201062. PMID9174053.
Hernández L, Pinyol M, Hernández S, Beà S, Pulford K, Rosenwald A, Lamant L, Falini B, Ott G, Mason DY, Delsol G, Campo E (Nov 1999). "TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations". Blood. 94 (9): 3265–8. PMID10556217.
Souttou B, Carvalho NB, Raulais D, Vigny M (Mar 2001). "Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway". The Journal of Biological Chemistry. 276 (12): 9526–31. doi:10.1074/jbc.M007333200. PMID11121404.
Simonitsch I, Polgar D, Hajek M, Duchek P, Skrzypek B, Fassl S, Lamprecht A, Schmidt G, Krupitza G, Cerni C (Jun 2001). "The cytoplasmic truncated receptor tyrosine kinase ALK homodimer immortalizes and cooperates with ras in cellular transformation". FASEB Journal. 15 (8): 1416–8. doi:10.1096/fj.00-0678fje. PMID11387242.
Zamo A, Chiarle R, Piva R, Howes J, Fan Y, Chilosi M, Levy DE, Inghirami G (Feb 2002). "Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death". Oncogene. 21 (7): 1038–47. doi:10.1038/sj.onc.1205152. PMID11850821.
Passoni L, Scardino A, Bertazzoli C, Gallo B, Coluccia AM, Lemonnier FA, Kosmatopoulos K, Gambacorti-Passerini C (Mar 2002). "ALK as a novel lymphoma-associated tumor antigen: identification of 2 HLA-A2.1-restricted CD8+ T-cell epitopes". Blood. 99 (6): 2100–6. doi:10.1182/blood.V99.6.2100. PMID11877285.
Bonvini P, Gastaldi T, Falini B, Rosolen A (Mar 2002). "Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin". Cancer Research. 62 (5): 1559–66. PMID11888936.
ten Berge RL, Meijer CJ, Dukers DF, Kummer JA, Bladergroen BA, Vos W, Hack CE, Ossenkoppele GJ, Oudejans JJ (Jun 2002). "Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma". Blood. 99 (12): 4540–6. doi:10.1182/blood.V99.12.4540. PMID12036886.
Dirks WG, Fähnrich S, Lis Y, Becker E, MacLeod RA, Drexler HG (Jul 2002). "Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines". International Journal of Cancer. 100 (1): 49–56. doi:10.1002/ijc.10435. PMID12115586.