Anaplastic lymphoma kinase
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| Location (UCSC) | Chr 2: 29.19 – 29.92 Mb | Chr 17: 72.18 – 72.91 Mb | |||||||
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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.[5][6]
Identification
Anaplastic lymphoma kinase (ALK) was originally discovered in 1994
The full-length protein ALK was identified in 1997 by two groups.
Since the original discovery of the receptor in mammals, several
The
Mechanism
Following binding of the ligand, the full-length receptor ALK
Phosphorylated ALK activates multiple downstream signal transduction pathways, including MAPK-ERK, PI3K-AKT, PLCγ, CRKL-C3G, and JAK-STAT.[37][19]
Function
The receptor ALK plays a pivotal role in
ALK is critical for
ALK regulates
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.[37][19]
Anaplastic large-cell lymphoma
The 2;5 chromosomal translocation is associated with approximately 60% of
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.[59] Patients with this ALK rearrangement have the following clinicopathologic characteristics: Young age at diagnosis (median 50 years), female gender, nonsmoker/light smoker, adenocarcinoma histology with specific morphologic patterns such as cribriform and solid signet ring, expression of thyroid transcription factor 1, tendency to metastasize to pleura or pericardium, frequently with more metastases than other molecular types, and predominantly metastases to the central nervous system.[60] 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.[59] 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.[61]
Gene rearrangements and overexpression in other tumours
- Familial cases of neuroblastoma[62]
- Adult[65][66] and pediatric[67][68] renal cell carcinomas
- Esophageal squamous cell carcinoma[69][70]
- Breast cancer,[71] notably the inflammatory subtype[72]
- Colonic adenocarcinoma[71]
- Anaplastic thyroid cancer[75]
ALK inhibitors
- Xalkori (crizotinib), produced by Pfizer, was approved by the FDA for treatment of late stage lung cancer on August 26, 2011.[76] 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%.
In patients affected by relapsed or refractory ALK+ Anaplastic Large Cell Lymphoma, crizotinib produced objective response rates ranging from 65% to 90% and 3 year progression free survival rates of 60-75%. No relapse of the lymphoma was ever observed after the initial 100 days of treatment. Treatment must be continued indefinitely at present.[77][78][79]
- 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.[80]
- 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.
See also
Notes and references
Notes
- ^ In 2020, a genome-wide association study (GWAS) was published of 47,102 people in the Estonian Genome Center of the University of Tartu (EGCUT) Biobank which compared the DNA of healthy thin individuals in the lowest 6th percentile of body mass index to the DNA of normal-weight individuals. This study identified a number of genetic variations of the ALK gene that were associated with thinness. As a next step, experiments in mice and Drosophila fruit flies showed that mice in which the ALK gene was knocked out had the similar activity and diet levels as normal mice, but had lower body fat and weight from early age into adulthood. This implies that inhibition of this kinase, already of interest as a chemotherapy for cancers associated with this gene, might be a way to prevent weight gain.
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000171094 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000055471 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 8122112.
- ^ a b "Entrez Gene: ALK anaplastic lymphoma kinase (Ki-1)".
- ^ PMID 8183550.
- ^ PMID 9053841.
- ^ PMID 9174053.
- ^ PMID 11442633.
- ^ S2CID 4428538.
- PMID 23667670.
- PMID 26418745.
- PMID 26630010.
- PMID 25331893.
- ^ S2CID 4425423.
- ^ S2CID 4424062.
- PMID 18674914.
- ^ S2CID 21345361.
- ^ PMID 8633037.
- ^ PMID 15226403.
- ^ S2CID 40978851.
- PMID 14563642.
- PMID 17483340.
- PMID 9819383.
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- ^ PMID 21949657.
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- ^ PMID 19459784.
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- ^ S2CID 2386055.
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- PMID 26536237.
- ^ PMID 30030398.
- PMID 32291952.
- S2CID 218762956.
- S2CID 24564015.
- ^ a b "VENTANA ALK (D5F3) CDx Assay". Diagnostics.
- PMID 34082691.
- PMID 21252716.
- PMID 18724359.
- S2CID 22808049.
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- S2CID 9387860.
- PMID 21076462.
- S2CID 39004672.
- PMID 17131471.
- PMID 18946602.
- ^ PMID 19737969.
- PMID 22215853.
- PMID 11809760.
- PMID 11278720.
- PMID 21596819.
- ^ "Xalkori Approved for Lung Cancer". FDA.
- ^ Gambacorti-Passerini CB, Dilda I, Giudici G, Perego A, Pavesi F, Guerra L, et al. Clinical activity of crizotinib in advanced, chemoresistant ALK+ lymphoma patients. 2010 Annual Meeting of the American Society of Hematology. Orlando, Florida.
- PMID 21345110.
- PMID 24491302.
- ^ "ZYKADIA (ceritinib) capsules, for oral use Initial U.S. Approval: 2014" (PDF). United States Food and Drug Administration.
Further reading
- Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ, et al. (March 1998). "ALK-positive lymphoma: a single disease with a broad spectrum of morphology". Blood. 91 (6): 2076–2084. PMID 9490693.
- Pulford K, Lamant L, Espinos E, Jiang Q, Xue L, Turturro F, et al. (December 2004). "The emerging normal and disease-related roles of anaplastic lymphoma kinase". Cellular and Molecular Life Sciences. 61 (23): 2939–2953. PMID 15583856.
- Hernández L, Pinyol M, Hernández S, Beà S, Pulford K, Rosenwald A, et al. (November 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): 3265–3268. PMID 10556217.
- Simonitsch I, Polgar D, Hajek M, Duchek P, Skrzypek B, Fassl S, et al. (June 2001). "The cytoplasmic truncated receptor tyrosine kinase ALK homodimer immortalizes and cooperates with ras in cellular transformation". FASEB Journal. 15 (8): 1416–1418. S2CID 44855189.
- Zamo A, Chiarle R, Piva R, Howes J, Fan Y, Chilosi M, et al. (February 2002). "Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death". Oncogene. 21 (7): 1038–1047. PMID 11850821.
- Passoni L, Scardino A, Bertazzoli C, Gallo B, Coluccia AM, Lemonnier FA, et al. (March 2002). "ALK as a novel lymphoma-associated tumor antigen: identification of 2 HLA-A2.1-restricted CD8+ T-cell epitopes". Blood. 99 (6): 2100–2106. PMID 11877285.
- Bonvini P, Gastaldi T, Falini B, Rosolen A (March 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): 1559–1566. PMID 11888936.
- Hernández L, Beà S, Bellosillo B, Pinyol M, Falini B, Carbone A, et al. (April 2002). "Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell lymphomas: identification of a new TFG-ALK(XL) chimeric gene with transforming activity". The American Journal of Pathology. 160 (4): 1487–1494. PMID 11943732.
- ten Berge RL, Meijer CJ, Dukers DF, Kummer JA, Bladergroen BA, Vos W, et al. (June 2002). "Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma". Blood. 99 (12): 4540–4546. PMID 12036886.
- Dirks WG, Fähnrich S, Lis Y, Becker E, MacLeod RA, Drexler HG (July 2002). "Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines". International Journal of Cancer. 100 (1): 49–56. S2CID 29955293.
External links
- ALK+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- ALK Correlations, Experiments, Publications and Clinical Trials
- GeneReviews/NCBI/NIH/UW entry on ALK-Related Neuroblastoma Susceptibility
- OMIM entries on ALK-Related Neuroblastoma Susceptibility
- Human ALK genome location and ALK gene details page in the UCSC Genome Browser.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
