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EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients.
Sabir SR
,
Yeoh S
,
Jackson G
,
Bayliss R
.
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Since the discovery of the fusion between EML4 (echinoderm microtubule associated protein-like 4) and ALK (anaplastic lymphoma kinase), EML4-ALK, in lung adenocarcinomas in 2007, and the subsequent identification of at least 15 different variants in lung cancers, there has been a revolution in molecular-targeted therapy that has transformed the outlook for these patients. Our recent focus has been on understanding how and why the expression of particular variants can affect biological and molecular properties of cancer cells, as well as identifying the key signalling pathways triggered, as a result. In the clinical setting, this understanding led to the discovery that the type of variant influences the response of patients to ALK therapy. Here, we discuss what we know so far about the EML4-ALK variants in molecular signalling pathways and what questions remain to be answered. In the longer term, this analysis may uncover ways to specifically treat patients for a better outcome.
Figure 1. Protein domain structures and functional motifs of echinoderm microtubule associated protein-like 4 (EML4), anaplastic lymphoma kinase (ALK), and EML4-ALK fusions. EML4 domains and motifs shown are: trimerisation domain (TD); hydrophobic motif in EML proteins (HELP); tandem atypical propeller domain (TAPE). ALK domains and motifs shown are: Meprin, A5 protein, and protein tyrosine phosphatase Mu domain (MAM); low-density lipoprotein receptor class A (LDLa); glycine-rich region (G-rich); transmembrane helix (TM); juxtamembrane domain (JM); tyrosine kinase domain (TK). Key interactions and functions are marked with arrows. Breakpoints in EML4 and ALK that generate EML4-ALK fusions are marked with red squares. Longer variants of the EML4-ALK fusion protein include an incomplete TAPE domain (e.g., v1, v2, v4’), whereas shorter variants include a few residues from the TAPE domain (v3) or no TAPE domain at all (v5).
Bulinski,
Self-assembly of microtubules in extracts of cultured HeLa cells and the identification of HeLa microtubule-associated proteins.
1979, Pubmed
Bulinski,
Self-assembly of microtubules in extracts of cultured HeLa cells and the identification of HeLa microtubule-associated proteins.
1979,
Pubmed
Camidge,
Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.
2012,
Pubmed
Cha,
Clinical outcomes in ALK-rearranged lung adenocarcinomas according to ALK fusion variants.
2016,
Pubmed
,
Echinobase
Choi,
Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer.
2008,
Pubmed
Choi,
EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.
2010,
Pubmed
,
Echinobase
Costa,
Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases.
2015,
Pubmed
Eichenmuller,
The human EMAP-like protein-70 (ELP70) is a microtubule destabilizer that localizes to the mitotic apparatus.
2002,
Pubmed
,
Echinobase
Ferlay,
Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
2015,
Pubmed
Fry,
EML proteins in microtubule regulation and human disease.
2016,
Pubmed
,
Echinobase
Hallberg,
The role of the ALK receptor in cancer biology.
2016,
Pubmed
,
Echinobase
Hanna,
Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy.
2004,
Pubmed
Heidebrecht,
Cloning and localization of C2orf2(ropp120), a previously unknown WD repeat protein.
2000,
Pubmed
Heuckmann,
Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants.
2012,
Pubmed
Horn,
EML4-ALK: honing in on a new target in non-small-cell lung cancer.
2009,
Pubmed
Katayama,
Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers.
2012,
Pubmed
Katayama,
Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK.
2011,
Pubmed
,
Echinobase
Katayama,
Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine.
2015,
Pubmed
Koivunen,
EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.
2008,
Pubmed
Kwak,
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
2010,
Pubmed
Lei,
Anaplastic Lymphoma Kinase Variants and the Percentage of ALK-Positive Tumor Cells and the Efficacy of Crizotinib in Advanced NSCLC.
2016,
Pubmed
,
Echinobase
Lin,
Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers.
2009,
Pubmed
,
Echinobase
Liu,
Recent Development in the Discovery of Anaplastic Lymphoma Kinase (ALK) Inhibitors for Non-small Cell Lung Cancer.
2017,
Pubmed
Morris,
Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.
1994,
Pubmed
Parkin,
Global cancer statistics, 2002.
2005,
Pubmed
Richards,
Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain.
2014,
Pubmed
,
Echinobase
Richards,
Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain.
2015,
Pubmed
,
Echinobase
Sanders,
Exon scanning by reverse transcriptase-polymerase chain reaction for detection of known and novel EML4-ALK fusion variants in non-small cell lung cancer.
2011,
Pubmed
Sasaki,
The biology and treatment of EML4-ALK non-small cell lung cancer.
2010,
Pubmed
,
Echinobase
Sequist,
Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer.
2010,
Pubmed
Shaw,
Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
2013,
Pubmed
Shaw,
Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.
2009,
Pubmed
Shaw,
Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.
2011,
Pubmed
Soda,
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
2007,
Pubmed
,
Echinobase
Soda,
A mouse model for EML4-ALK-positive lung cancer.
2008,
Pubmed
Soda,
A prospective PCR-based screening for the EML4-ALK oncogene in non-small cell lung cancer.
2012,
Pubmed
Solomon,
First-line crizotinib versus chemotherapy in ALK-positive lung cancer.
2014,
Pubmed
Suprenant,
EMAP, an echinoderm microtubule-associated protein found in microtubule-ribosome complexes.
1993,
Pubmed
,
Echinobase
Suprenant,
Conservation of the WD-repeat, microtubule-binding protein, EMAP, in sea urchins, humans, and the nematode C. elegans.
2000,
Pubmed
,
Echinobase
Takeuchi,
Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts.
2008,
Pubmed
Takeuchi,
KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer.
2009,
Pubmed
Thun,
The global burden of cancer: priorities for prevention.
2010,
Pubmed
Woo,
Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer.
2017,
Pubmed
,
Echinobase
Yoshida,
Differential Crizotinib Response Duration Among ALK Fusion Variants in ALK-Positive Non-Small-Cell Lung Cancer.
2016,
Pubmed
Zhang,
Coupling an EML4-ALK-centric interactome with RNA interference identifies sensitizers to ALK inhibitors.
2016,
Pubmed
