The emerging pathogenic and therapeutic importance of the anaplastic lymphoma kinase gene

doi:10.1016/j.ejca.2010.04.006

European Journal of Cancer

Volume 46, Issue 13, September 2010, Pages 2357-2368

https://doi.org/10.1016/j.ejca.2010.04.006 Get rights and content

Abstract

The anaplastic lymphoma kinase gene (ALK) is a gene on chromosome 2p23 that has expression restricted to the brain, testis and small intestine but is not expressed in normal lymphoid tissue. It has similarity to the insulin receptor subfamily of kinases and is emerging as having increased pathologic and potential therapeutic importance in malignant disease. This gene was originally established as being implicated in the pathogenesis of rare diseases including inflammatory myofibroblastic tumour (IMT) and ALK-positive anaplastic large cell lymphoma, which is a subtype of non-Hodgkin’s lymphoma. Recently the number of diseases in which ALK is implicated in their pathogenesis has increased. In 2007, an inversion of chromosome 2 involving ALK and a fusion partner gene in a subset of non-small cell lung cancer was discovered.¹ In 2008, publications emerged implicating ALK in familial and sporadic cases of neuroblastoma, a childhood cancer of the sympatho-adrenal system.2, 3, 4, 5

Chromosomal abnormalities involving ALK are translocations, amplifications or mutations. Chromosomal translocations are the longest recognised ALK genetic abnormality. When translocations occur a fusion gene is created between ALK and a gene partner. This has been described in ALK-positive anaplastic large cell lymphoma in which ALK is fused to NPM (nucleolar protein gene) and in non-small cell lung cancer where ALK is fused to EML4 (Echinoderm microtubule-associated protein 4). The most frequently described partner genes in inflammatory myofibroblastic tumour are tropomyosin 3/4 (TMP3/4), however in IMTs a diversity of ALK fusion partners have been found, with the ability to homodimerise a common characteristic.⁶ Point mutations and amplification of the ALK gene occur in the childhood cancer neuroblastoma. Therapeutic targeting of ALK fusion genes using tyrosine kinase inhibition, vaccination using an ALK specific antigen and treatment using viral vectors for RNAi are emerging potential therapeutic possibilities.

Section snippets

The ALK gene in physiology and development

The anaplastic lymphoma kinase (ALK) is a 200 kDa receptor tyrosine kinase that is a member of the insulin receptor superfamily encoded by the ALK gene located on chromosome 2p23⁹ (Fig. 2 is illustrative of the ALK gene structure and potential mechanisms of drug resistance).

ALK is normally expressed in the developing nervous system and at lower concentration in the nervous system of adult. Evidence from studies of Drosophila indicates an additional role in visceral muscle differentiation.

ALK is

Anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL) is a rare lymphoma in adults accounting for 2% of cases and is more frequent in the paediatric population comprising 25% of lymphomas in children. It is a form of Non Hodgkin’s lymphoma. The immunophenotype of anaplastic large cell/null cell lymphoma is usually CD3+, CD30+, EMA+ and ALK+. Tumour cells will be CD20- and CD15-.¹⁵ The expression of CD30 or Ki-1 is a classic diagnostic immunophenotypic marker and was first described by Stein in 1982. Ki-1 is a

Neuroblastoma

Neuroblastoma is a childhood cancer that occurs most frequently in the first year of life and descends in frequency thereafter with a median age of diagnosis of nineteen months. Epidemiologically neuroblastoma has an age standardised incidence rate in Europe of 10.9 cases per million children (52.6 in infants) with an average overall survival of 59% in the period 1978–1997.²¹ The molecular characteristics of neuroblastoma have been extensively investigated and some have been correlated with

Inflammatory myofibroblastic tumour

Inflammatory myofibroblastic tumours are tumours of uncertain pathogenesis that comprise mesenchymal proliferations of myofibroblasts with inflammatory infiltrates of eosinophils, plasma cells and lymphocytes. They occur primarily in children and young adults. Cytogenesis banding studies have shown that approximately 50% of IMT have clonal rearrangements of chromosome 2 and recurrent involvement of 2p23 the locus for ALK occurs in inflammatory myofibroblastic tumours.³² Tropomyosin TMP3 and

Non-small cell lung cancer

Lung cancer is the most common malignancy and consists of non-small cell lung cancer (NSCLC) and small cell lung cancer with frequencies of 85 and 15%, respectively. Treatment of non-small cell lung cancer with cytotoxic chemotherapy is of limited therapeutic benefit. EGFR inhibitors can be therapeutically beneficial in cases of NSCLC with activating mutations in the epidermal growth factor (EGFR) gene in exons 18, 19 and 21.33, 34 These account for approximately 8–9% of NSCLC and are more

ALK-directed therapeutics

Therapeutics directed at the chimeric fusion gene: small molecules RNA inhibition and tumour vaccination.

ALK-directed therapeutics means that ALK inhibition may be used to effectively treat cancers emerging from differing tissues. In ALK+ anaplastic large cell lymphoma, three molecularly targeted treatment approaches emerge. Firstly, like the inhibition of BCR-ABL using imatinib mesylate in chronic myeloid leukaemia, small molecule inhibition of the fusion gene NPM–ALK can downregulate

Potential synergistic therapeutics

Therapeutic strategies directed against ALK but not specific for it have emergent possible therapeutic benefits in cancer treatment. These include IGF-IR interaction with NPM–ALK, GSK 1838705A, an inhibitor of IGF-IR, the insulin receptor and ALK and PF-02341066 an inhibitor of c-Met/HGFR and the ALK receptor tyrosine kinase. Also pre-clinical data suggest an expansion of ALK-directed therapeutics.

‘ALKoma’ a new member of haemato-oncologic molecular disease

Like other receptor tyrosine kinases, ALK may be activated by chromosomal translocations, genomic amplification or point mutations.⁵² Chromosomal translocations appear to be the most frequent genomic abnormality involving the ALK gene. Fusion gene products in haematological disease have been recognised for decades with the finding of the Philadelphia chromosome by Nowell and Hungerford in 1960 and the description of the chromosome (9:22) BCR-ABL translocation by Rowley in 1973.53, 54 This

Conflict of interest statement

None declared.

Acknowledgement

The author F. Kelleher wishes to acknowledge Professor John Crown, Consultant Medical Oncologist, St. Vincent’s University Hospital, Dublin, Ireland, for exceptional lifesaving medical care that he received from him. The authors’ subsequent recovery to good health allowed the completion of this article.

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Due to the lack of effective therapies, identification of novel therapeutic targets for high-risk NB is urgently needed [3,4]. Anaplastic lymphoma kinase (ALK), known as ALK tyrosine kinase receptor or cluster of differentiation 246 (CD246), has been identified as one of the major oncogenes in tumor pathogenesis [5–11]. In NB, high expression levels of ALK closely correlates with poor outcomes, especially in high-risk NB [12–14].
Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time. These results indicate that alectinib may be a promising therapeutic agent for the treatment of NB.
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View full text

ReviewThe emerging pathogenic and therapeutic importance of the anaplastic lymphoma kinase gene

Abstract

Section snippets

The ALK gene in physiology and development

Anaplastic large cell lymphoma

Neuroblastoma

Inflammatory myofibroblastic tumour

Non-small cell lung cancer

ALK-directed therapeutics

Potential synergistic therapeutics

‘ALKoma’ a new member of haemato-oncologic molecular disease

Conflict of interest statement

Acknowledgement

Blood

Blood

Blood

Lancet

Thorac Oncol

Am J Pathol

Cell

Mod Pathol

J Thorac Oncol

Blood

Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer

Nature

Identification of ALK as a major familial neuroblastoma predisposition gene. Identification of ALK as a major familial neuroblastoma predisposition gene

Nature

Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma

Nature

Activating mutations in ALK provide a therapeutic target in neuroblastoma

Nature

Oncogenic mutations of ALK kinase in neuroblastoma

Nature

Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumour

Genes Chromosomes Cancer

Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy

Expert Rev Anticancer Ther

Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in oesophageal cancer

World J Gastroenterol

Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma

Science

Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system

Oncogene

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

The emerging normal and disease-related roles of anaplastic lymphoma kinase

Cell Mol Life Sci

ALK is a novel dependence receptor: potential implications in development and cancer

Cell Cycle

Anaplastic lymphoma kinase is a dependence receptor whose proapoptotic functions are activated by caspase cleavage

Mol Cell Biol

Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma

Science

ALK a novel lymphoma-associated tumour antigen for vaccination strategies

Leuk Lymphoma

Prevalence and functional consequence of PHOX2B mutations in neuroblastoma

Oncogene

Review
The emerging pathogenic and therapeutic importance of the anaplastic lymphoma kinase gene