Affinage

EML4

Echinoderm microtubule-associated protein-like 4 · UniProt Q9HC35

Length
981 aa
Mass
108.9 kDa
Annotated
2026-06-09
100 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EML4 is a microtubule-associated protein whose N-terminal trimerization domain and adjacent basic region drive self-association and binding to the acidic C-terminal tails of α/β-tubulin, an activity governed in mitosis by NEK6/NEK7-mediated phosphorylation of Ser144/Ser146 that lowers microtubule affinity and prevents hyperstabilization and chromosome congression defects (PMID:25740311, PMID:31409757). Clinically, EML4 is best characterized through the oncogenic EML4-ALK fusion produced by inv(2)(p21p23), in which the EML4 N-terminal portion confers constitutive ALK kinase activation through trimeric self-association, transforming cells in vitro and driving lung adenocarcinoma in vivo in a kinase-dependent manner (PMID:17625570, PMID:19064915, PMID:25740311). The EML4 moiety also promotes the fusion protein's assembly into cytoplasmic condensates via liquid-liquid phase separation dependent on aromatic residues in the EML4 region; these condensates concentrate MAPK, PLCγ and PI3K signalling components and sequester the RTK adapters GRB2 and SOS1, coupling ALK activity to downstream STAT3 phosphorylation, malignant transformation, and suppression of basal RTK signalling (PMID:33976114, PMID:34661367, PMID:39488530). EML4-ALK engages RAS-MAPK signalling through the EML4 HELP domain, which binds all three RAS isoforms, and activates JAK-STAT and PI3K-AKT cascades that drive PD-L1 induction, lineage plasticity, and resistance phenotypes (PMID:26301689, PMID:34090412, PMID:38284990). Fusion variants differ in protein stability, microtubule localization, and condensate behavior—variant 3 retains the EML4 microtubule-binding region and recruits NEK9/NEK7 to microtubules to promote microtubule stabilization and cell migration independently of ALK activity—accounting for variant-specific signalling and inhibitor sensitivity (PMID:22912387, PMID:32184261, PMID:34661367).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2007 High

    Established that a recurrent chromosomal inversion fuses EML4 to ALK and that the product is a bona fide oncogene, defining a new actionable driver in NSCLC.

    Evidence Retroviral cDNA expression library focus-formation screen, RT-PCR, and nude-mouse xenograft of the fusion

    PMID:17625570

    Open questions at the time
    • Did not define how the EML4 portion activates ALK
    • No structural basis for activation
  2. 2008 Medium

    Showed that the EML4 coiled-coil region mediates constitutive oligomerization of the fusion, providing the first mechanistic explanation for ligand-independent ALK activation.

    Evidence Biochemical oligomerization analysis with focus formation and in vivo tumour assays

    PMID:19032370

    Open questions at the time
    • Stoichiometry of self-association not resolved
    • Synthesis/review-level detail rather than primary structural data
  3. 2008 High

    Identified multiple EML4-ALK fusion variants and demonstrated their transforming activity and pharmacological dependence on ALK catalytic activity, motivating ALK-targeted therapy.

    Evidence RT-PCR isoform discovery, focus formation, in vivo tumour assays, ALK inhibitor treatment of patient-derived cells, IHC

    PMID:18593892 PMID:18927303 PMID:19064915

    Open questions at the time
    • Why variants differ functionally was not addressed
    • Cell-of-origin not defined
  4. 2012 High

    Linked fusion variant identity to differential protein stability and inhibitor/HSP90 sensitivity, and placed downstream survival signalling on parallel STAT3 and ERK arms.

    Evidence Ba/F3 variant constructs with cytotoxicity, protein-stability, and localization assays; combination ALK/MEK inhibitor signalling studies in NSCLC lines

    PMID:22240786 PMID:22912387

    Open questions at the time
    • Structural basis of variant stability differences unresolved
    • Did not establish condensate involvement
  5. 2015 High

    Defined the EML4 trimerization domain structurally and showed it is necessary and sufficient for self-association and, with the basic region, for microtubule binding, unifying ALK activation with EML4's native cytoskeletal role.

    Evidence X-ray crystallography of EML2/EML4 coiled-coils, domain-deletion mutagenesis, microtubule binding and immunofluorescence in H2228 cells

    PMID:25740311

    Open questions at the time
    • Did not resolve how microtubule binding contributes to oncogenic signalling
    • Phase separation not yet implicated
  6. 2015 High

    Mapped EML4-ALK engagement of RAS-MAPK to the EML4 HELP domain and connected RAS-MAPK reactivation to acquired ALK inhibitor resistance, and showed EML4-ALK drives PD-L1, EMT, and bypass resistance through MAPK/PI3K and paracrine ligands.

    Evidence HELP-domain deletion constructs, RAS pull-downs, MEK-combination studies in cells/mice and patients; PD-L1 flow cytometry; co-culture paracrine resistance assays; EMT and stem-cell marker assays

    PMID:22553343 PMID:25735977 PMID:26019170 PMID:26301689 PMID:27141364

    Open questions at the time
    • Spatial organization of these signalling outputs not yet explained
    • Relative contribution of each downstream arm to tumour maintenance unclear
  7. 2017 High

    Revealed a post-translational regulatory input by which SMYD2-mediated methylation of ALK residues supports fusion phosphorylation and AKT-driven growth.

    Evidence In vitro methyltransferase assay, SMYD2 knockdown, K→A mutagenesis, pALK/pAKT Western blot and growth assays

    PMID:28370702

    Open questions at the time
    • Methylation site falls in the ALK rather than EML4 moiety
    • Single-lab, in vitro plus cell-based only
  8. 2019 High

    Established native EML4 as a tubulin-tail-binding microtubule-associated protein regulated by mitotic NEK6/NEK7 phosphorylation at Ser144/Ser146, defining its physiological function in mitotic microtubule dynamics.

    Evidence Cryo-EM reconstruction, microtubule sedimentation, in vitro NEK6/NEK7 kinase assays, S144A/S146A mutagenesis, RNAi, live-cell chromosome congression imaging

    PMID:31409757

    Open questions at the time
    • How this regulation is co-opted in the fusion context not directly tested
    • Other kinase inputs not excluded
  9. 2020 High

    Showed that variant 3 EML4-ALK recruits NEK9/NEK7 to microtubules to stabilize them and drive migration independently of ALK kinase activity, revealing an ALK-independent EML4-driven mechanism of aggressiveness.

    Evidence EML4-ALK V3 cell models, immunofluorescence, migration assays, NEK9/NEK7 activation and microtubule-depolymerization rescue

    PMID:32184261

    Open questions at the time
    • Whether this pathway is targetable clinically untested here
    • Generalizability to other variants unclear
  10. 2021 High

    Demonstrated that EML4-ALK forms phase-separated cytoplasmic condensates that concentrate MAPK/PLCγ/PI3K components and require an active ALK conformation, with aromatic EML4 residues driving phase separation, STAT3 signalling, and tumourigenesis.

    Evidence Phase-separation imaging in cells/GEMMs/organoids, aromatic-residue and salt-bridge mutagenesis, inhibitor-induced foci dissolution, STAT3 and tumour assays

    PMID:33976114 PMID:34090412 PMID:34661367

    Open questions at the time
    • Quantitative link between condensate material state and signalling output incompletely defined
    • Variant-specific condensate differences only partly mapped
  11. 2024 High

    Connected condensate biology to therapy resistance: condensates sequester GRB2/SOS1 to suppress basal RTK signalling, and ALK inhibition releases adapters and pulsatile paracrine ERK reactivation, while phase-separation-driven JAK-STAT signalling promotes adeno-to-squamous lineage transition.

    Evidence Optogenetic condensate manipulation, GRB2/SOS1 sequestration and ERK reporter assays, paracrine blockade; GEMMs, organoids, scRNA-seq and JAK-STAT inhibition for lineage transition

    PMID:38284990 PMID:39488530

    Open questions at the time
    • Long-term clinical efficacy of paracrine/JAK-STAT combination strategies not established
    • Determinants of squamous-transition cell-of-origin specificity incompletely defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how native full-length EML4 microtubule and NEK regulation mechanistically intersect with fusion condensate formation to determine variant-specific signalling and durable resistance.
  • No unified model linking microtubule localization, condensate state, and downstream pathway selection
  • Physiological (non-fusion) EML4 functions beyond mitosis uncharacterized in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0060089 molecular transducer activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005829 cytosol 3 GO:0005856 cytoskeleton 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2 R-HSA-1640170 Cell Cycle 1
Partners
ALKGRB2NEK6NEK7NEK9RASSMYD2SOS1

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 A small inversion within chromosome 2p [inv(2)(p21p23)] generates a fusion gene comprising portions of EML4 and ALK in NSCLC cells. Expression of the EML4-ALK fusion tyrosine kinase in mouse 3T3 fibroblasts produced transformed foci in culture and subcutaneous tumours in nude mice, demonstrating its oncogenic activity. Retroviral cDNA expression library functional screening (focus formation assay), RT-PCR, forced expression in NIH3T3 cells, nude mouse xenograft Nature High 17625570
2008 EML4-ALK oligomerizes constitutively in cells through the coiled-coil (dimerization) domain within the EML4 region, leading to constitutive activation of ALK kinase activity and oncogenicity both in vitro and in vivo. Biochemical analysis of fusion protein oligomerization, focus formation assay, in vivo tumour model Cancer science Medium 19032370
2008 EML4-ALK variants 3a and 3b (exon 6 of EML4 fused to exon 20 of ALK) exhibit marked transforming activity in vitro and oncogenic activity in vivo; a lung cancer cell line expressing endogenous variant 3 undergoes cell death upon treatment with a specific ALK catalytic activity inhibitor. RT-PCR identification of novel isoforms, focus formation assay, in vivo tumour assay, ALK inhibitor treatment of patient-derived cell line Cancer research High 18593892
2008 EML4-ALK fusion drives lung adenocarcinoma formation in transgenic mice expressing the kinase specifically in lung alveolar epithelial cells; ALK kinase inhibitor treatment caused rapid disappearance of tumours, confirming essential kinase-dependent oncogenic role in vivo. Transgenic mouse model with lung-specific EML4-ALK expression, oral ALK inhibitor treatment, histopathology Proceedings of the National Academy of Sciences of the United States of America High 19064915
2008 Novel EML4-ALK isoforms containing exon 14 (variant 4) or exon 2 (variant 5) of EML4 fused to ALK exon 20 were identified; both variants manifest marked oncogenic activity and produce a cytoplasmic staining pattern with fine granular foci. Multiplex RT-PCR, genomic PCR, FISH, focus formation assay, immunohistochemistry Clinical cancer research High 18927303
2012 Different EML4-ALK fusion variants (v1, v2, v3a, v3b) exhibit differential sensitivity to ALK kinase inhibitors crizotinib and TAE684, correlating with differences in protein stability. Sensitivity to HSP90 inhibition also varies by fusion variant. Combining ALK and HSP90 inhibitors produces synergistic cytotoxicity. Ba/F3 cell line model, cytotoxicity assays, protein stability measurements, HSP90 inhibitor treatment, intracellular localization studies Clinical cancer research High 22912387
2012 In EML4-ALK-positive H2228 NSCLC cells, the ALK inhibitor TAE684 inhibits STAT3 but not ERK phosphorylation, yielding little effect on apoptosis alone; combining TAE684 with a MEK inhibitor induces marked apoptosis through simultaneous inhibition of STAT3-survivin and ERK-BIM pathways. Cell proliferation assay, Western blot for pSTAT3/pERK/survivin/BIM, apoptosis assay in NSCLC cell lines British journal of cancer Medium 22240786
2015 EML4-ALK activates RAS-MAPK signaling by engaging all three major RAS isoforms (HRAS, KRAS, NRAS) through the HELP domain of EML4. RAS-MAPK reactivation (via KRAS copy gain or reduced DUSP6) drives ALK inhibitor resistance in vitro and in patients. Genetic epistasis experiments, HELP domain deletion constructs, RAS isoform pull-down, patient biopsy analysis, MEK inhibitor combination studies in cell lines and mouse models Nature medicine High 26301689
2015 EML4-ALK upregulates PD-L1 expression in NSCLC cells via activation of the MEK-ERK and PI3K-AKT signaling pathways. Forced EML4-ALK expression in Ba/F3 cells markedly increases PD-L1; ALK inhibition or ALK siRNA attenuates PD-L1 expression. Flow cytometry, RT-PCR, forced EML4-ALK expression in Ba/F3, RNAi knockdown, pathway inhibitor treatment (MEK-ERK, PI3K-AKT), immunohistochemistry Clinical cancer research High 26019170
2015 EML4 proteins require an N-terminal trimerization domain (TD) for self-association. Crystal structures of the coiled-coil/TD from EML2 and EML4 reveal a trimeric oligomerization state driven by conserved hydrophobic residues and salt bridges, providing the structural basis for EML4-ALK constitutive activation. The TD is necessary and sufficient for self-association and is also essential for microtubule binding (requiring an adjacent basic region). EML4-ALK variant 3, which includes the TD and basic region but lacks WD40 repeats, localises to microtubules in recombinant systems and in patient-derived H2228 NSCLC cells. X-ray crystallography (crystal structures of EML2 and EML4 coiled-coils), domain deletion mutagenesis, self-association assay, microtubule binding assay, immunofluorescence in NSCLC cell line The Biochemical journal High 25740311
2015 EML4-ALK enhances PD-L1 expression through HIF-1α and STAT3 under both normoxia and hypoxia. EML4-ALK increases HIF-1α expression by increasing its transcription and decreasing its ubiquitination. Transfection of EML4-ALK into H23 cells, ALK knockdown/crizotinib in H2228 cells, HIF-1α transcription/ubiquitination assays, STAT3 inhibitor treatment, immunofluorescence, immunohistochemistry in patient tissues Oncoimmunology Medium 27141364
2017 SMYD2 lysine methyltransferase methylates ALK at lysine residues K1451, K1455, and K1610. SMYD2 knockdown or inhibition reduces phosphorylation of EML4-ALK protein. Substitution of K1610 with alanine reduces AKT phosphorylation and suppresses growth of EML4-ALK-positive NSCLC cells. In vitro methyltransferase assay, SMYD2 knockdown, site-directed mutagenesis (K→A), Western blot for pALK and pAKT, cell growth assay Cancer science High 28370702
2019 EML4 is a microtubule-associated protein whose N-terminal basic domain mediates binding to the acidic C-terminal tails of α- and β-tubulin on the microtubule surface (revealed by microtubule sedimentation and cryo-EM). In mitosis, NEK6 and NEK7 phosphorylate the EML4 N-terminal domain at Ser144 and Ser146, reducing microtubule affinity; depletion of NEK6/7 increases mitotic EML4-microtubule binding, and an S144A-S146A double mutant causes microtubule hyperstabilisation and chromosome congression defects. Cryo-electron microscopy with 3D reconstruction, microtubule sedimentation assay, in vitro kinase assay (NEK6/NEK7), site-directed mutagenesis, RNAi depletion, live-cell imaging of chromosome congression Science signaling High 31409757
2020 EML4-ALK variant 3 (V3), which includes the N-terminal EML4 microtubule-binding region, recruits the NEK9 and NEK7 kinases to microtubules, causes microtubule stabilisation, formation of extended cytoplasmic protrusions, and increased cell migration. Constitutive activation of NEK9 perturbs cell morphology and accelerates migration in a microtubule-dependent, NEK7-dependent manner that does not require ALK activity. Cell line models expressing EML4-ALK V3, immunofluorescence, migration assays, NEK9/NEK7 overexpression/activation, microtubule depolymerisation rescue experiments Journal of cell science High 32184261
2021 EML4-ALK variant 1 forms cytoplasmic condensates via liquid-liquid phase separation. Mutation of multiple aromatic residues in the EML4 region impairs phase separation, dampens downstream STAT3 phosphorylation, and significantly decreases malignant transformation and tumour formation in GEMMs. Phase separation imaging in cancer cell lines and GEMMs, organoid models, aromatic-residue mutagenesis, STAT3 phosphorylation assay, focus formation and in vivo tumour assay Cell discovery High 33976114
2021 EML4-ALK V1 and V3 proteins form cytoplasmic foci containing components of MAPK, PLCγ and PI3K signalling pathways. ALK inhibitors ceritinib and lorlatinib dissolve these foci; V3 but not V1 protein re-localises to microtubules upon inhibitor treatment, recapitulated by a catalytically inactive EML4-ALK mutant. Alectinib increases foci formation of both wild-type and catalytically inactive V3 but not a Lys-Glu salt-bridge mutant. Foci formation requires an active ALK kinase conformation. Live-cell imaging of EML4-ALK foci, inhibitor treatment, catalytically inactive mutant, salt-bridge mutagenesis, subcellular fractionation/microtubule co-localisation, immunofluorescence EMBO reports High 34661367
2021 EML4-ALK activates the JAK2-STAT signalling pathway; JAK2, STAT1, STAT3, STAT5, and STAT6 are constitutively phosphorylated in EML4-ALK-expressing cells. Co-immunoprecipitation and immunofluorescence show activated STAT6 and JAK2 co-localise with ALK. EML4-ALK knockdown reduces STAT6 phosphorylation and decreases cell proliferation/viability. Signalling pathway microarray, Western blot, co-immunoprecipitation, immunofluorescence, siRNA knockdown, cell viability assay BMC pulmonary medicine Medium 34090412
2022 EML4-ALK G1202R mutation induces epithelial-mesenchymal transition (EMT) and ceritinib resistance by activating the STAT3/Slug signalling pathway, upregulating STAT3 and Slug expression; combination of ALK and STAT3 inhibitors restores ceritinib sensitivity. Stable expression of EML4-ALK G1202R in A549 cells, migration/invasion assays, Western blot for STAT3/pSTAT3/Slug/EMT markers, combination inhibitor treatment Cellular signalling Medium 35085771
2024 EML4-ALK assemblies (condensates) sequester RTK adapter proteins GRB2 and SOS1, suppressing transmembrane RTK signalling. ALK inhibition dissolves condensates, releases sequestered adapters, and thereby resensitises RTK signalling; this releases pulsatile ERK reactivation driven by paracrine ligands from dying cells, promoting drug tolerance. Combination therapies blocking paracrine signalling counteract this survival mechanism. Optogenetics to manipulate EML4-ALK condensates, live-cell imaging, GRB2/SOS1 co-localisation and sequestration assays, ERK activity reporters, paracrine ligand blockade experiments Nature communications High 39488530
2024 EML4-ALK phase separation activates JAK-STAT signalling, which promotes adeno-to-squamous lineage transition in lung tumours. Club cells are identified as the main cell-of-origin for squamous transition. JAK1/2 inhibitor combined with ALK inhibitor overcomes resistance associated with squamous transition. Transgenic mouse models (GEMMs), lung organoid recapitulation of lineage transition, scRNA-seq, immunostaining, JAK-STAT pathway inhibition, patient tissue analysis The Journal of experimental medicine High 38284990
2015 EML4-ALK-positive NSCLC cells are sensitive to ALK inhibitors; EGFR ligands (EGF, TGF-α, HB-EGF) activate EGFR and trigger bypass resistance to crizotinib and TAE684 via ERK1/2 and AKT. HGF activates Met/Gab1 and triggers resistance to TAE684 but not crizotinib. Paracrine supply of these ligands by endothelial cells and fibroblasts recapitulates resistance in co-culture. Cell viability assay, Western blot for pEGFR/pMet/pERK/pAKT, co-culture with endothelial cells and fibroblasts, EGFR-TKI and Met-TKI rescue experiments, in vivo xenograft Clinical cancer research (originally 2012 published) Medium 22553343
2015 EML4-ALK induces EMT and cancer stem cell-like properties (elevated CD133, enhanced mammosphere formation) in H1299 NSCLC cells; ERK1/2 inhibition reverses the EMT phenotype, placing ERK downstream of EML4-ALK in this process. Stable EML4-ALK expression in H1299 cells, invasion/migration assay, stem cell marker (CD133) quantification, mammosphere assay, ERK inhibitor treatment Biochemical and biophysical research communications Medium 25735977

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 4311 17625570
2009 Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1569 19667264
2008 EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 839 18594010
2009 The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 593 19170230
2010 The biology and treatment of EML4-ALK non-small cell lung cancer. European journal of cancer (Oxford, England : 1990) 436 20418096
2008 A mouse model for EML4-ALK-positive lung cancer. Proceedings of the National Academy of Sciences of the United States of America 421 19064915
2008 Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clinical cancer research : an official journal of the American Association for Cancer Research 418 18927303
2015 Induction of PD-L1 Expression by the EML4-ALK Oncoprotein and Downstream Signaling Pathways in Non-Small Cell Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 401 26019170
2019 Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non-Small Cell Lung Cancer in the Global Phase III ALEX Study. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 377 30902613
2008 Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer research 370 18593892
2018 Impact of EML4-ALK Variant on Resistance Mechanisms and Clinical Outcomes in ALK-Positive Lung Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 287 29373100
2010 Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene. Annals of surgical oncology 274 20183914
2009 EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. The American journal of pathology 260 19147828
2009 Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers. Molecular cancer research : MCR 252 19737969
2010 Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression. Molecular cancer 249 20624322
2015 RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nature medicine 243 26301689
2012 Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants. Clinical cancer research : an official journal of the American Association for Cancer Research 231 22912387
2008 EML4-ALK fusion lung cancer: a rare acquired event. Neoplasia (New York, N.Y.) 200 18320074
2008 Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer. Cancer science 189 19032370
2017 Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer. Annals of oncology : official journal of the European Society for Medical Oncology 186 28039177
2012 EML4-ALK testing in non-small cell carcinomas of the lung: a review with recommendations. Virchows Archiv : an international journal of pathology 169 22825000
2016 Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer. Oncotarget 164 26544515
2017 EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients. Cancers 149 28872581
2015 EML4-ALK enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor (HIF)-1α and STAT3. Oncoimmunology 136 27141364
2008 EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas. Lung cancer (Amsterdam, Netherlands) 135 18242762
2018 Circular RNA F-circEA-2a derived from EML4-ALK fusion gene promotes cell migration and invasion in non-small cell lung cancer. Molecular cancer 124 30236141
2017 Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 124 29099503
2015 Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: Implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients. Oncoimmunology 122 27141355
2012 Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells. Clinical cancer research : an official journal of the American Association for Cancer Research 106 22553343
2013 Clinical significance of EML4-ALK fusion gene and association with EGFR and KRAS gene mutations in 208 Chinese patients with non-small cell lung cancer. PloS one 105 23341890
2021 Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC. Lung cancer (Amsterdam, Netherlands) 103 34175504
2016 Molecular mechanisms that underpin EML4-ALK driven cancers and their response to targeted drugs. Cellular and molecular life sciences : CMLS 86 26755435
2012 EML4-ALK translocation predicts better outcome in lung adenocarcinoma patients with wild-type EGFR. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 84 22124476
2015 Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain. The Biochemical journal 80 25740311
2015 Nonsquamous, Non-Small-Cell Lung Cancer Patients Who Carry a Double Mutation of EGFR, EML4-ALK or KRAS: Frequency, Clinical-Pathological Characteristics, and Response to Therapy. Clinical lung cancer 76 26712101
2011 Exon scanning by reverse transcriptase-polymerase chain reaction for detection of known and novel EML4-ALK fusion variants in non-small cell lung cancer. Cancer genetics 72 21356191
2022 EML4-ALK fusion gene in non-small cell lung cancer. Oncology letters 69 35928804
2021 Phase separation of EML4-ALK in firing downstream signaling and promoting lung tumorigenesis. Cell discovery 63 33976114
2011 Evaluation of EML4-ALK fusion proteins in non-small cell lung cancer using small molecule inhibitors. Neoplasia (New York, N.Y.) 57 21245935
2023 EML4-ALK biology and drug resistance in non-small cell lung cancer: a new phase of discoveries. Molecular oncology 56 37149843
2014 Concordance of IHC, FISH and RT-PCR for EML4-ALK rearrangements. Translational lung cancer research 56 25806283
2008 EML4-ALK fusion transcript is not found in gastrointestinal and breast cancers. British journal of cancer 55 18414414
2021 Phase-separated foci of EML4-ALK facilitate signalling and depend upon an active kinase conformation. EMBO reports 54 34661367
2013 Analysis of EGFR, EML4-ALK, KRAS, and c-MET mutations in Chinese lung adenocarcinoma patients. Experimental lung research 52 23919423
2015 Clinicopathological characteristics of patients with non-small-cell lung cancer who harbor EML4-ALK fusion gene: a meta-analysis. PloS one 49 25706305
2014 ALK/EML4 fusion gene may be found in pure squamous carcinoma of the lung. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 49 24722159
2014 Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells. Oncotarget 47 24952482
2014 Metformin and salinomycin as the best combination for the eradication of NSCLC monolayer cells and their alveospheres (cancer stem cells) irrespective of EGFR, KRAS, EML4/ALK and LKB1 status. Oncotarget 47 25375092
2023 Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 Mutations. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 45 37541389
2012 Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small-cell lung cancer cells. British journal of cancer 45 22240786
2015 Synergistic effects of crizotinib and radiotherapy in experimental EML4-ALK fusion positive lung cancer. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 44 25592111
2018 Oncogene addiction and radiation oncology: effect of radiotherapy with photons and carbon ions in ALK-EML4 translocated NSCLC. Radiation oncology (London, England) 43 29304828
2015 Clinical and epidemiological study of EGFR mutations and EML4-ALK fusion genes among Indian patients with adenocarcinoma of the lung. OncoTargets and therapy 42 25609979
2013 Detection of EGFR mutations and EML4-ALK rearrangements in lung adenocarcinomas using archived cytological slides. Cancer cytopathology 41 23408463
2014 Overcoming the resistance to crizotinib in patients with non-small cell lung cancer harboring EML4/ALK translocation. Lung cancer (Amsterdam, Netherlands) 40 24598368
2012 EML4-ALK rearrangement and its clinical significance in Chinese patients with advanced non-small cell lung cancer. Oncology 39 22964709
2020 EML4-ALK V3 oncogenic fusion proteins promote microtubule stabilization and accelerated migration through NEK9 and NEK7. Journal of cell science 38 32184261
2019 Mitotic phosphorylation by NEK6 and NEK7 reduces the microtubule affinity of EML4 to promote chromosome congression. Science signaling 38 31409757
2020 Distribution of EML4-ALK fusion variants and clinical outcomes in patients with resected non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 36 33017727
2017 Effects of SMYD2-mediated EML4-ALK methylation on the signaling pathway and growth in non-small-cell lung cancer cells. Cancer science 36 28370702
2023 Catalytic Degraders Effectively Address Kinase Site Mutations in EML4-ALK Oncogenic Fusions. Journal of medicinal chemistry 35 37036171
2015 In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line. Cancer science 32 25581823
2017 Concomitant EML4-ALK rearrangement and EGFR mutation in non-small cell lung cancer patients: a literature review of 100 cases. Oncotarget 31 28938691
2015 EML4-ALK induces epithelial-mesenchymal transition consistent with cancer stem cell properties in H1299 non-small cell lung cancer cells. Biochemical and biophysical research communications 30 25735977
2012 The biology and clinical features of non-small cell lung cancers with EML4-ALK translocation. Current oncology reports 30 22311682
2014 Clinicopathologic features of patients with non-small cell lung cancer harboring the EML4-ALK fusion gene: a meta-analysis. PloS one 29 25360721
2011 New targets in advanced NSCLC: EML4-ALK. Clinical advances in hematology & oncology : H&O 29 21475126
2021 A fully automated assay to detect the expression of pan-cytokeratins and of EML4-ALK fusion protein in circulating tumour cells (CTCs) predicts outcome of non-small cell lung cancer (NSCLC) patients. Translational lung cancer research 28 33569295
2018 Dual target gene therapy to EML4-ALK NSCLC by a gold nanoshell-based system. Theranostics 27 29774063
2016 ALK-positive large B-cell lymphoma: identification of EML4-ALK and a review of the literature focusing on the ALK immunohistochemical staining pattern. International journal of hematology 27 26781614
2021 Targeting EML4-ALK gene fusion variant 3 in thyroid cancer. Endocrine-related cancer 26 33878728
2016 Establishment of a Conditional Transgenic Mouse Model Recapitulating EML4-ALK-Positive Human Non-Small Cell Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 26 27836576
2022 EML4-ALK G1202R mutation induces EMT and confers resistance to ceritinib in NSCLC cells via activation of STAT3/Slug signaling. Cellular signalling 25 35085771
2019 Concomitant EGFR Mutation and EML4-ALK Rearrangement in Lung Adenocarcinoma Is More Frequent in Multifocal Lesions. Clinical lung cancer 24 31138506
2019 EML4-ALK translocation identification in RNA exosomal cargo (ExoALK) in NSCLC patients: a novel role for liquid biopsy. Translational cancer research 24 35117067
2014 Sensitive and specific detection of EML4-ALK rearrangements in non-small cell lung cancer (NSCLC) specimens by multiplex amplicon RNA massive parallel sequencing. Lung cancer (Amsterdam, Netherlands) 24 24674157
2019 miR-100-5p confers resistance to ALK tyrosine kinase inhibitors Crizotinib and Lorlatinib in EML4-ALK positive NSCLC. Biochemical and biophysical research communications 23 30791979
2013 Pulmonary inflammatory myofibroblastic tumor harboring EML4-ALK fusion gene. Japanese journal of clinical oncology 23 24277751
2021 EML4-ALK-mediated activation of the JAK2-STAT pathway is critical for non-small cell lung cancer transformation. BMC pulmonary medicine 22 34090412
2020 Spindle cell tumor with CD34 and S100 co-expression and distinctive stromal and perivascular hyalinization showing EML4-ALK fusion. Journal of cutaneous pathology 22 33241586
2020 Effective RNA Knockdown Using CRISPR-Cas13a and Molecular Targeting of the EML4-ALK Transcript in H3122 Lung Cancer Cells. International journal of molecular sciences 21 33255340
2012 EML4-ALK fusion gene in Korean non-small cell lung cancer. Journal of Korean medical science 21 22323876
2023 Durable responses to alectinib in murine models of EML4-ALK lung cancer requires adaptive immunity. NPJ precision oncology 20 36739466
2015 The EML4-ALK oncogene: targeting an essential growth driver in human cancer. Proceedings of the Japan Academy. Series B, Physical and biological sciences 19 25971657
2022 EML4-NTRK3 Fusion Cervical Sarcoma: A Case Report and Literature Review. Frontiers in medicine 18 35572973
2022 Role of chemokine-mediated angiogenesis in resistance towards crizotinib and its reversal by anlotinib in EML4-ALK positive NSCLC. Journal of translational medicine 18 35642002
2019 Genome-wide meta-analysis identifies BARX1 and EML4-MTA3 as new loci associated with infantile hypertrophic pyloric stenosis. Human molecular genetics 18 30281099
2021 Colorectal Cancer with EML4-ALK Fusion Gene Response to Alectinib: A Case Report and Review of the Literature. Case reports in oncology 17 33776709
2020 Spindle cell neoplasm with EML4-ALK gene fusion presenting as an intraosseous vertebral mass. Genes, chromosomes & cancer 17 33170538
2024 EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation. The Journal of experimental medicine 16 38284990
2020 Comparison of EML4-ALK fusion gene positive rate in different detection methods and samples of non-small cell lung cancer. Journal of Cancer 16 32047559
2014 Combined point mutation in KRAS or EGFR genes and EML4-ALK translocation in lung cancer patients. Future oncology (London, England) 15 24754584
2024 Oncogenic EML4-ALK assemblies suppress growth factor perception and modulate drug tolerance. Nature communications 14 39488530
2023 Transformation of NSCLC to SCLC harboring EML4-ALK fusion with V1180L mutation after alectinib resistance and response to lorlatinib: A case report and literature review. Lung cancer (Amsterdam, Netherlands) 14 37907052
2022 Case Report: Early Distant Metastatic Inflammatory Myofibroblastic Tumor Harboring EML4-ALK Fusion Gene: Study of Two Typical Cases and Review of Literature. Frontiers in medicine 14 35280868
2021 ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells. Scientific reports 14 33907223
2020 Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition. EMBO molecular medicine 14 32558295
2017 Dual drive coexistence of EML4-ALK and TPM3-ROS1 fusion in advanced lung adenocarcinoma. Thoracic cancer 14 29251824
2014 Non-small cell lung cancer with EML4-ALK translocation in Chinese male never-smokers is characterized with early-onset. BMC cancer 14 25407901
2023 Discovery of potent and effective inhibitors containing sulfoxide structures targeting EML4-ALK rearrangement and EGFR mutant non-small cell lung cancer. Bioorganic chemistry 13 37302317

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