Affinage

ALK

ALK tyrosine kinase receptor · UniProt Q9UM73

Length
1620 aa
Mass
176.4 kDa
Annotated
2026-06-09
100 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALK is a receptor tyrosine kinase that drives oncogenic transformation when its C-terminal kinase domain is fused to N-terminal partners that supply dimerization motifs, generating constitutively active fusion oncoproteins whose subcellular localization is dictated by the fusion partner (PMID:10934142, PMID:27874193). In anaplastic large cell lymphoma and related malignancies, fusion proteins such as NPM-ALK, TPM3/4-ALK, and SEC31A-ALK signal through STAT3, ERK1/2, AKT, and STAT5; STAT3 activation is kinase-dependent and transcriptionally upregulates anti-apoptotic Bcl-xL and, via direct promoter binding, HIF1α (PMID:11850821, PMID:21102525, PMID:20207848). These fusions are sufficient to initiate and are required to maintain tumors, since genetic or pharmacological ALK inactivation drives sustained regression (PMID:20223922). ALK signaling also engages additional effectors: it binds the adaptor IRS-1 to couple into the IGF-1R pathway (PMID:25173427), positively regulates MYC transcription and transactivation (PMID:29507657), and its activity is restrained by the phosphatases PTPN1 and PTPN2, which directly bind and dephosphorylate ALK and limit SHP2-driven downstream signaling (PMID:34657149). Beyond fusion-driven cancers, point mutations in the ALK kinase domain constitutively activate the receptor in neuroblastoma (PMID:25517749), where ligand-mediated activation by ALKAL2 is itself sufficient to drive tumorigenesis (PMID:33411331) and ALK signaling supports an ATR/CHK1 DNA damage response (PMID:38154064). ALK additionally has non-oncogenic physiological and immune roles: it interacts with EGFR to activate AKT/IRF3/NF-κB and STING-dependent innate immunity in monocytes and macrophages (PMID:29046432), and hypothalamic ALK controls energy expenditure and adipose lipolysis, with its loss conferring resistance to obesity (PMID:32442405). Resistance to ALK kinase inhibitors arises through secondary kinase-domain mutations, bypass activation of EGFR, IGF-1R, or AXL signaling, and loss of restraining phosphatases (PMID:21791641, PMID:25173427, PMID:34657149, PMID:26616860).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2000 High

    Established that ALK becomes oncogenic by fusion of its kinase domain to partner-derived coiled-coil domains, generating constitutively active proteins whose localization tracks the partner.

    Evidence Molecular cloning, Western blot, and in vitro kinase assays of TPM3/4-ALK fusions in inflammatory myofibroblastic tumors

    PMID:10934142

    Open questions at the time
    • Did not define the full downstream signaling cascade
    • Limited to a single tumor type
  2. 2002 High

    Resolved how fusion ALK signals for survival by showing kinase-dependent direct STAT3 phosphorylation upregulates anti-apoptotic Bcl-xL.

    Evidence Wild-type vs kinase-dead NPM-ALK K210R in BaF3 cells, inhibitor studies, and ALCL tissue immunohistochemistry

    PMID:11850821

    Open questions at the time
    • Jak3 binding observed but dispensable, leaving the kinase upstream of STAT3 undefined
    • Did not address other parallel pathways
  3. 2010 High

    Demonstrated ALK fusions are both sufficient to initiate and required to maintain lymphoma, validating ALK as a therapeutic target.

    Evidence Conditional doxycycline-inducible transgenic mice with NPM-ALK and TPM3-ALK plus PF-2341066 inhibition

    PMID:20223922

    Open questions at the time
    • Did not test fusion partners beyond NPM and TPM3
    • Mechanism of regression not dissected at signaling level
  4. 2010 High

    Extended ALK fusion signaling to transcriptional control of HIF1α via STAT3 binding to its promoter under normoxia.

    Evidence Kinase-dead mutant, ChIP, and STAT3/HIF1α siRNA in BaF3 and ALK+ TCL cells

    PMID:21102525

    Open questions at the time
    • Functional consequence of HIF1α-mediated mTORC1 suppression in vivo not established
  5. 2010 Medium

    Showed additional fusions (SEC31A-ALK) transform cells and converge on ERK/AKT/STAT3/STAT5 effectors.

    Evidence Ba/F3 transformation assay with TAE-684 inhibition and downstream phospho-profiling

    PMID:20207848

    Open questions at the time
    • Single cell-line model
    • No in vivo confirmation
  6. 2011 High

    Defined two mechanisms of acquired resistance: a secondary kinase-domain mutation (L1152R) and EGFR bypass signaling, and showed dual inhibition overcomes both.

    Evidence Sequencing of patient-derived and engineered resistant cell lines with ALK/EGFR combination studies

    PMID:21791641

    Open questions at the time
    • Prevalence of each mechanism in patients not quantified
    • Other bypass pathways not surveyed
  7. 2012 Medium

    Linked EML4-ALK fusion variant identity to differential inhibitor and HSP90 sensitivity through protein stability differences.

    Evidence Ba/F3 lines expressing v1/v2/v3a/v3b with cytotoxicity, localization, stability, and HSP90 combination assays

    PMID:22912387

    Open questions at the time
    • Single lab
    • Clinical correlation of variant-specific sensitivity not established
  8. 2014 High

    Identified IRS-1 as a direct ALK fusion partner coupling ALK to IGF-1R signaling and an inhibitor resistance pathway.

    Evidence Co-IP, IRS-1 siRNA, ALK/IGF-1R combination in resistant models, and patient biopsies

    PMID:25173427

    Open questions at the time
    • Reciprocal validation of binding limited
    • Stoichiometry of IRS-1 engagement unknown
  9. 2014 High

    Distinguished oncogenic from non-oncogenic ALK kinase-domain mutations in neuroblastoma and tied them to differential crizotinib sensitivity.

    Evidence Genomic analysis of 1,596 neuroblastomas with biochemical kinase activity and crizotinib assays

    PMID:25517749

    Open questions at the time
    • Structural basis of inhibitor resistance per mutation not fully resolved
  10. 2015 Medium

    Showed AXL/GAS6-driven EMT as a bypass resistance mechanism in ALK(F1174L) neuroblastoma.

    Evidence Resistant cell lines, AXL/TWIST2 overexpression, AXL inhibition, and GAS6 analysis

    PMID:26616860

    Open questions at the time
    • Single lab
    • In vivo and patient confirmation of AXL resistance limited
  11. 2016 High

    Cataloged diverse IMT fusion partners and reinforced that partner identity dictates ALK subcellular localization.

    Evidence ALK immunoprecipitation, mass spectrometry partner identification, and IHC localization including novel RRBP1-ALK

    PMID:27874193

    Open questions at the time
    • Functional signaling differences between localization patterns not tested
  12. 2017 Medium

    Revealed a non-oncogenic immune role: ALK interacts with EGFR to drive AKT/IRF3/NF-κB and STING-dependent innate immunity.

    Evidence Co-IP, ALK knockdown/knockout in monocytes/macrophages, and murine endotoxemia/sepsis models

    PMID:29046432

    Open questions at the time
    • Single lab
    • Direct ALK-EGFR binding not reciprocally validated
    • Ligand or activation trigger in immune cells undefined
  13. 2018 Medium

    Placed MYC downstream of ALK as a transcriptional effector and crizotinib-response determinant in NSCLC.

    Evidence Whole-genome shRNA screen, MYC RNAi and small-molecule inhibition, and MYC target transcriptional analysis

    PMID:29507657

    Open questions at the time
    • Single lab
    • Direct vs indirect transcriptional regulation not separated
  14. 2018 Medium

    Connected ALK signaling to the DNA damage response via ATR/CHK1 phosphorylation and showed combined ALK/ATR inhibition drives lineage differentiation.

    Evidence Genetically modified mouse neuroblastoma models with biochemical phospho-readouts and lineage marker analysis

    PMID:38154064

    Open questions at the time
    • Single lab
    • Direct vs indirect ATR phosphorylation not resolved
  15. 2018 Medium

    Demonstrated ALK fusion proteins can be eliminated by PROTAC-induced VHL-dependent degradation rather than catalytic inhibition.

    Evidence Ceritinib-VHL PROTAC (TD-004) degradation assays in SU-DHL-1/H3122 cells and H3122 xenografts

    PMID:30274779

    Open questions at the time
    • Single lab
    • Activity against resistant kinase-domain mutants not shown
  16. 2020 High

    Defined a physiological role for ALK in hypothalamic control of energy expenditure and adipose lipolysis.

    Evidence GWAS in thin individuals, Drosophila RNAi, and Alk-deleted mice with energy expenditure and lipolysis measurements

    PMID:32442405

    Open questions at the time
    • Endogenous ligand and downstream neuronal circuitry not fully mapped
  17. 2021 Medium

    Showed ligand-mediated ALK activation by ALKAL2 is sufficient to drive neuroblastoma without ALK mutation.

    Evidence ALKAL2-overexpressing transgenic mice with ALK TKI treatment

    PMID:33411331

    Open questions at the time
    • Single lab
    • Relative contribution of autocrine vs paracrine ALKAL2 not resolved
  18. 2021 Medium

    Established that ALK inhibition induces immunogenic cell death on-target in ALK+ ALCL, linking ALK targeting to anti-tumor immunity.

    Evidence ICD marker assays, ALK siRNA, resistance mutants, and in vivo vaccination/rechallenge in immunocompetent mice

    PMID:34272360

    Open questions at the time
    • Single lab
    • Generalizability beyond ALCL not tested
  19. 2022 High

    Identified PTPN1/PTPN2 as direct ALK-binding phosphatases that restrain ALK and whose loss drives TKI resistance via SHP2 hyperactivation.

    Evidence Genome-wide LOF screens, Co-IP, phosphatase assays, in vivo resistance models, patient RNA-seq, and SHP2 inhibitor combination

    PMID:34657149

    Open questions at the time
    • Direct dephosphorylation site mapping on ALK incomplete
  20. 2023 Medium

    Showed ALK inhibitors upregulate surface ALK to enable ALK-targeted CAR-T efficacy against low-expression neuroblastoma.

    Evidence ALK.CAR-T development, flow cytometry for surface ALK after inhibitor treatment, and xenograft combination studies

    PMID:38039964

    Open questions at the time
    • Single lab
    • Mechanism of inhibitor-induced surface upregulation undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis by which ALKAL2 ligand and partner-driven dimerization activate the wild-type ALK ectodomain, and how endogenous ALK signaling is regulated across its physiological versus oncogenic contexts, remains incompletely defined.
  • No structural model of ligand-bound full-length receptor in the corpus
  • Endogenous ALK signaling outputs in normal neurons not mechanistically mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0060089 molecular transducer activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2 GO:0005635 nuclear envelope 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 5 R-HSA-168256 Immune System 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-1430728 Metabolism 1
Partners
ALKAL2EGFRIRS-1PTPN1PTPN2SHP2STAT3

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 NPM-ALK (nucleophosmin-anaplastic lymphoma kinase) fusion protein constitutively activates Stat3 through direct phosphorylation; ALK also binds and activates Jak3, but Jak3 is not required for Stat3 activation or in vitro transformation. Constitutive Stat3 activation by NPM-ALK upregulates Bcl-xL transcription, providing anti-apoptotic signals that protect cells from death. Transfection of wild-type and kinase-inactive NPM-ALK K210R mutant into BaF3 cells; immunohistochemistry on primary human ALCLs; inhibitor studies (Jak/Stat pathway inhibitors); functional rescue assays Oncogene High 11850821
2000 In inflammatory myofibroblastic tumors, tropomyosin (TPM3 and TPM4) N-terminal coiled-coil domains fuse to the ALK C-terminal kinase domain, producing ~95 kDa fusion oncoproteins with constitutive kinase activity and tyrosine phosphorylation. The subcellular localization of ALK fusion proteins depends on the localization of the fusion partner. Molecular cloning of fusion genes; Western blotting demonstrating ~95 kDa proteins; in vitro kinase assays demonstrating constitutive activity; immunohistochemistry correlating ALK localization with fusion partner identity The American Journal of Pathology High 10934142
2010 NPM-ALK and TPM3-ALK oncoproteins are sufficient to induce lymphoma/leukemia (early B-cell arrest and lymphomagenesis) in vivo in conditional transgenic mice and are required for tumor maintenance; inactivation of the ALK oncogene by doxycycline or pharmacological ALK inhibition (PF-2341066) causes sustained tumor regression. Conditional transgenic mouse models (tetracycline-inducible expression under EmuSRα promoter); doxycycline-mediated oncogene inactivation; treatment with specific ALK inhibitor PF-2341066 in vivo Blood High 20223922
2010 NPM-ALK constitutively activates Stat3, which binds to the HIF1α gene promoter and drives HIF1α mRNA transcription under normoxia. NPM-ALK-induced HIF1α expression requires the enzymatic activity of NPM-ALK and is mediated through Stat3; HIF1α in turn suppresses mTORC1 activation and regulates VEGF synthesis. BaF3 cells transfected with wild-type and kinase-inactive NPM-ALK K210R mutant; ALK inhibitor treatment of ALK+ TCL cells; chromatin immunoprecipitation (ChIP) demonstrating Stat3 binding to HIF1α promoter; siRNA-mediated depletion of STAT3 and HIF1α Oncogene High 21102525
2012 Different EML4-ALK fusion variants (v1, v2, v3a, v3b) exhibit differential sensitivity to ALK kinase inhibitors (crizotinib, TAE684) that correlates with differences in protein stability. Sensitivity to HSP90 inhibition also varies by fusion partner and differs from ALK inhibitor sensitivity patterns. Combining ALK and HSP90 inhibitors results in synergistic cytotoxicity. Ba/F3 cell line model expressing different EML4-ALK variants; cytotoxicity assays; intracellular localization studies; protein stability measurements; HSP90 inhibitor combination studies Clinical Cancer Research Medium 22912387
2011 Resistance to ALK tyrosine kinase inhibitors arises via two mechanisms: (1) a secondary L1152R ALK kinase domain mutation that confers resistance to both crizotinib and TAE684, and (2) coactivation of EGFR signaling as a bypass pathway independent of ALK mutation. Dual inhibition of both ALK and EGFR is the most effective therapeutic strategy for cells with either resistance mechanism. Sequencing of resistant tumor biopsy and resistant cell line derived from a crizotinib-treated patient; generation of TAE684-resistant H3122 cell line (TR3); pharmacological combination studies with ALK and EGFR inhibitors Cancer Research High 21791641
2014 ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), engaging the IGF-1R signaling pathway. IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In ALK TKI-resistant models, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Co-immunoprecipitation of ALK fusion proteins with IRS-1; siRNA knockdown of IRS-1; pharmacological combination studies in ALK TKI-resistant models; biopsy analysis from patients progressing on crizotinib Nature Medicine High 25173427
2014 ALK tyrosine kinase domain mutations in neuroblastoma at three hotspots confer constitutive kinase activation (oncogenic mutations) and show differential sensitivity to crizotinib in vitro. Biochemical and computational analyses distinguish oncogenic from non-oncogenic mutations. Comprehensive genomic analysis of 1,596 neuroblastoma samples; biochemical assays measuring kinase activity; computational prediction; in vitro crizotinib sensitivity assays Cancer Cell High 25517749
2017 ALK directly interacts with EGFR to trigger AKT (serine-threonine kinase) phosphorylation and activate IRF3 and NF-κB signaling pathways in monocytes and macrophages, enabling STING-dependent inflammatory responses to cyclic dinucleotides. Genetic disruption of ALK diminishes STING-mediated innate immune responses. Co-immunoprecipitation demonstrating ALK-EGFR interaction; genetic knockdown/knockout of ALK in monocytes/macrophages; pharmacological and genetic inhibition of the ALK-STING pathway in murine endotoxemia and sepsis models Science Translational Medicine Medium 29046432
2020 ALK expression in hypothalamic neurons controls energy expenditure via sympathetic control of adipose tissue lipolysis. Genetic deletion of ALK in mice results in thin animals with marked resistance to diet- and leptin-mutation-induced obesity. GWAS on thin individuals; RNAi-mediated knockdown of Alk in Drosophila (decreased triglyceride levels); genetic deletion of Alk in mice; measurement of energy expenditure and adipose tissue lipolysis Cell High 32442405
2016 ALK fusions found in inflammatory myofibroblastic tumors (conventional and atypical) include TPM3/4-ALK, DCTN1-ALK, TFG-ALK, RANBP2-ALK, and a novel RRBP1-ALK fusion. RRBP1-ALK shows cytoplasmic ALK expression with perinuclear accentuation (distinct from the nuclear membranous pattern of RANBP2-ALK), demonstrating that fusion partner identity determines subcellular localization of ALK oncoprotein. ALK immunoprecipitation from tumor lysates; electrophoresis; mass spectrometry characterization of ALK fusion partners; immunohistochemistry for ALK localization The Journal of Pathology High 27874193
2022 PTPN1 and PTPN2 phosphatases bind to ALK and regulate its phosphorylation and activity. Oncogenic ALK and STAT3 repress PTPN1 transcription (creating a feedback loop). PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Loss of PTPN1 or PTPN2 induces ALK TKI resistance by hyperactivating SHP2, MAPK, and JAK/STAT pathways. Genomic loss-of-function screens; Co-immunoprecipitation demonstrating PTPN1/PTPN2 binding to ALK; phosphatase activity assays; in vitro and in vivo resistance models; RNA sequencing of patient samples with TKI resistance; pharmacological combination of crizotinib with SHP2 inhibitor Blood High 34657149
2010 The SEC31A-ALK fusion transforms IL3-dependent Ba/F3 cells to growth factor independence, and the ALK inhibitor TAE-684 reduces cell proliferation and kinase activity of SEC31A-ALK and its downstream effectors ERK1/2, AKT, STAT3, and STAT5. Ba/F3 cell transformation assay; pharmacological inhibition with TAE-684; measurement of downstream effector phosphorylation (ERK1/2, AKT, STAT3, STAT5) Haematologica Medium 20207848
2018 ALK signaling in neuroblastoma leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. Combined ALK/ATR inhibition results in robust and sustained tumor response, whereas ATR inhibition alone yields initial response followed by relapse. The sustained response to combined inhibition reflects differentiation of tumor cells toward neuronal/Schwann cell lineage identity. Genetically modified mouse neuroblastoma models; biochemical measurement of ATR and CHK1 phosphorylation downstream of ALK signaling; in vivo treatment with ALK inhibitor, ATR inhibitor, and combination; lineage marker analysis Proceedings of the National Academy of Sciences of the United States of America Medium 38154064
2021 ALKAL2 ligand overexpression drives ALK TKI-sensitive neuroblastoma in the absence of ALK mutation in mice, demonstrating that ligand-mediated (paracrine/autocrine) ALK activation is sufficient for neuroblastoma development and progression. Transgenic mouse model with ALKAL2 overexpression; ALK TKI treatment of resulting tumors; comparison with ALK mutation-driven models The EMBO Journal Medium 33411331
2015 ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT). AXL phosphorylation confers resistance through upregulated ERK signaling. AXL activation is mediated through increased expression of its ligand GAS6, which also stabilizes the AXL protein. AXL overexpression (but not TWIST2 overexpression alone) induces ALK inhibitor resistance. Generation of TAE684/LDK378-resistant neuroblastoma cell lines; Western blotting for AXL and downstream signaling; AXL inhibition studies; ectopic overexpression of AXL and TWIST2; GAS6 ligand analysis; HSP90 inhibitor studies Oncogene Medium 26616860
2018 ALK positively regulates transcriptional expression of MYC and activates c-MYC transactivation of c-MYC target genes in ALK-positive NSCLC. MYCBP was identified as a determinant of crizotinib response by genome-wide shRNA screen, and inhibition of MYC by RNAi or small molecules sensitizes ALK+ cells to crizotinib. Whole-genome shRNA loss-of-function screen; RNAi knockdown of MYC; small-molecule MYC inhibition; transcriptional analysis of MYC target genes following ALK inhibition Oncotarget Medium 29507657
2021 Pharmacological inhibition of ALK (by crizotinib or ceritinib) in ALK-positive ALCL induces immunogenic cell death (ICD), characterized by calreticulin surface exposure, ATP release, HMGB1 release, and type I interferon response. This ICD induction is on-target: it is mimicked by ALK knockdown, lost with resistance-conferring ALK mutants, and replicated by inhibiting downstream ALK signaling pathways. In vivo, ceritinib-treated ALK+ ALCL cells vaccinated immunocompetent mice and protected against rechallenge in an antigen-specific manner. ICD marker assays (calreticulin exposure, ATP/HMGB1 release); ALK siRNA knockdown; resistance-conferring ALK mutant cell lines; in vivo vaccination/rechallenge experiments in immunocompetent vs. immunodeficient mice; PD-1 blockade combination Cell Death & Disease Medium 34272360
2023 ALK inhibitors upregulate ALK expression on neuroblastoma cell surfaces while impairing tumor growth, thereby facilitating the activity of ALK-targeted CAR-T cells. The combination of ALK inhibitors with ALK.CAR-T cells shows potent efficacy specifically against neuroblastoma with low ALK expression, whereas neither modality alone is sufficient. ALK.CAR-T cell development and testing in vitro and in vivo; flow cytometry for ALK surface expression after inhibitor treatment; combination efficacy studies in neuroblastoma xenograft models Cancer Cell Medium 38039964
2018 PROTAC molecules (TD-004) composed of ceritinib (ALK inhibitor) linked to a VHL E3 ligase ligand effectively induce ALK fusion protein (NPM-ALK and EML4-ALK) degradation via the ubiquitin-proteasome system, inhibit growth of ALK fusion-positive cell lines, and significantly reduce tumor growth in H3122 xenograft models. PROTAC molecule design and synthesis; cell-based ALK degradation assays in SU-DHL-1 and H3122 cells; xenograft tumor growth assay Biochemical and Biophysical Research Communications Medium 30274779

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 RET, ROS1 and ALK fusions in lung cancer. Nature medicine 1068 22327623
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
2011 Identification of genes upregulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. Cancer research 749 22080568
2000 TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. The American journal of pathology 534 10934142
2011 A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer research 510 21791641
1999 ALK+ lymphoma: clinico-pathological findings and outcome. Blood 456 10194450
2017 Targeting ALK: Precision Medicine Takes on Drug Resistance. Cancer discovery 422 28122866
2001 Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study. The American journal of surgical pathology 400 11684952
2002 Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death. Oncogene 321 11850821
2014 ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer cell 305 25517749
2016 The role of the ALK receptor in cancer biology. Annals of oncology : official journal of the European Society for Medical Oncology 284 27573755
2014 Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nature medicine 241 25173427
2012 Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition. Pharmacological research 232 23201355
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
2018 Resistance Mechanisms to Targeted Therapies in ROS1+ and ALK+ Non-small Cell Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 216 29636358
2001 Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 213 11607814
2000 Expression of the ALK tyrosine kinase gene in neuroblastoma. The American journal of pathology 168 10793082
1999 Lymphomas expressing ALK fusion protein(s) other than NPM-ALK. Blood 157 10552961
2013 ALK inhibitors in the treatment of advanced NSCLC. Cancer treatment reviews 154 23931927
2019 Treatment with Next-Generation ALK Inhibitors Fuels Plasma ALK Mutation Diversity. Clinical cancer research : an official journal of the American Association for Cancer Research 129 31358542
2022 ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition. Blood 128 34727172
2015 Intratumoral Heterogeneity of ALK-Rearranged and ALK/EGFR Coaltered Lung Adenocarcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 122 26416997
2017 ALK is a therapeutic target for lethal sepsis. Science translational medicine 114 29046432
2018 ALK in Neuroblastoma: Biological and Therapeutic Implications. Cancers 112 29642598
2015 Entrectinib: a potent new TRK, ROS1, and ALK inhibitor. Expert opinion on investigational drugs 110 26457764
2008 Development of anaplastic lymphoma kinase (ALK) small-molecule inhibitors for cancer therapy. Medicinal research reviews 110 17694547
2019 Prediction of ALK mutations mediating ALK-TKIs resistance and drug re-purposing to overcome the resistance. EBioMedicine 107 30662002
2016 ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma. The Journal of pathology 107 27874193
2018 Identification of ALK Rearrangements in Malignant Peritoneal Mesothelioma. JAMA oncology 104 28910456
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
2018 Induced protein degradation of anaplastic lymphoma kinase (ALK) by proteolysis targeting chimera (PROTAC). Biochemical and biophysical research communications 102 30274779
2019 Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK). Journal of medicinal chemistry 100 31419130
2017 Anaplastic lymphoma kinase (ALK) inhibitors in the treatment of ALK-driven lung cancers. Pharmacological research 100 28077299
2015 ALK rearrangement and overexpression in epithelioid fibrous histiocytoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 98 25857825
2011 Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP. Journal of hematology & oncology 98 21504625
2015 ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT. Oncogene 96 26616860
2011 Emerging importance of ALK in neuroblastoma. Seminars in cancer biology 89 21945349
2011 Crizotinib and testing for ALK. Journal of the National Comprehensive Cancer Network : JNCCN 89 22157554
2015 Anaplastic large cell lymphomas: ALK positive, ALK negative, and primary cutaneous. Advances in anatomic pathology 86 25461779
2021 Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer. Nature communications 83 33627640
2014 HIP1-ALK, a novel ALK fusion variant that responds to crizotinib. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 83 24496003
2019 The Transcriptional Roles of ALK Fusion Proteins in Tumorigenesis. Cancers 75 31366041
2023 Targeted therapy for lung cancer: Beyond EGFR and ALK. Cancer 74 37073562
2020 Identification of ALK in Thinness. Cell 72 32442405
2019 ALK Inhibitors in the Treatment of ALK Positive NSCLC. Frontiers in oncology 69 30687633
2010 ALK-positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions. Haematologica 69 20207848
2017 Crizotinib in ALK+ inflammatory myofibroblastic tumors-Current experience and future perspectives. Pediatric blood & cancer 66 29286567
2023 Genomic ALK alterations in primary and relapsed neuroblastoma. British journal of cancer 58 36807339
2018 Anaplastic Lymphoma Kinase (ALK) Receptor Tyrosine Kinase: A Catalytic Receptor with Many Faces. International journal of molecular sciences 57 30400214
2011 Oncogenic mutations of ALK in neuroblastoma. Cancer science 50 21205076
2019 Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity. Journal of medicinal chemistry 47 30789735
2014 Prospective screening for ALK: clinical features and outcome according to ALK status. European journal of cancer (Oxford, England : 1990) 47 24589437
2012 ALK-immunoreactive neoplasms. International journal of clinical and experimental pathology 46 22808292
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
2021 Therapeutic Sequencing in ALK+ NSCLC. Pharmaceuticals (Basel, Switzerland) 45 33494549
2023 ALK peptide vaccination restores the immunogenicity of ALK-rearranged non-small cell lung cancer. Nature cancer 42 37430060
2021 ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of ALK mutation. The EMBO journal 42 33411331
2023 ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells. Cancer cell 40 38039964
2020 Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression. Clinical cancer research : an official journal of the American Association for Cancer Research 40 33310890
2022 Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK+ anaplastic large cell lymphoma. Blood 38 34657149
2014 Development of anaplastic lymphoma kinase (ALK) inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer. OncoTargets and therapy 38 24623980
2021 Impact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors. JCO precision oncology 37 34036223
2020 ALK variants, PD-L1 expression, and their association with outcomes in ALK-positive NSCLC patients. Scientific reports 37 33273548
2019 Alectinib, an Anaplastic Lymphoma Kinase Inhibitor, Abolishes ALK Activity and Growth in ALK-Positive Neuroblastoma Cells. Frontiers in oncology 37 31334113
2018 Histologic transformation of ALK-rearranged adenocarcinoma to squamous cell carcinoma after treatment with ALK inhibitor. Lung cancer (Amsterdam, Netherlands) 36 30642554
2021 Deciphering the immunosuppressive tumor microenvironment in ALK- and EGFR-positive lung adenocarcinoma. Cancer immunology, immunotherapy : CII 35 34125345
2019 Defining molecular risk in ALK+ NSCLC. Oncotarget 35 31139322
2018 The ALK receptor in sympathetic neuron development and neuroblastoma. Cell and tissue research 34 29374774
2018 ALK (D5F3) CDx: an immunohistochemistry assay to identify ALK-positive NSCLC patients. Pharmacogenomics and personalized medicine 34 30271189
2016 Anaplastic Lymphoma Kinase (ALK) Kinase Domain Mutation Following ALK Inhibitor(s) Failure in Advanced ALK Positive Non-Small-Cell Lung Cancer: Analysis and Literature Review. Clinical lung cancer 33 27130468
2021 Pharmacological inhibitors of anaplastic lymphoma kinase (ALK) induce immunogenic cell death through on-target effects. Cell death & disease 32 34272360
2016 Overcoming crizotinib resistance in ALK-rearranged NSCLC with the second-generation ALK-inhibitor ceritinib. Expert review of anticancer therapy 32 26654422
2002 Anaplastic lymphoma kinase (ALK) protein expressing lymphoma after liver transplantation: case report and literature review. Journal of clinical pathology 31 12401829
2010 Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA. Oncogene 30 21102525
2018 Discovery and Characterization of Recurrent, Targetable ALK Fusions in Leiomyosarcoma. Molecular cancer research : MCR 29 30518629
2023 Update of Diagnosis and Targeted Therapy for ALK+ Inflammation Myofibroblastic Tumor. Current treatment options in oncology 28 37938503
2017 The heterogeneous landscape of ALK negative ALCL. Oncotarget 28 28061468
2016 The renal effects of ALK inhibitors. Investigational new drugs 28 27468827
2016 ALK alterations and inhibition in lung cancer. Seminars in cancer biology 28 27637426
2017 Targeting Anaplastic Lymphoma Kinase (ALK) in Rhabdomyosarcoma (RMS) with the Second-Generation ALK Inhibitor Ceritinib. Targeted oncology 27 29067644
2022 Activity of ALK Inhibitors in Renal Cancer with ALK Alterations: A Systematic Review. International journal of molecular sciences 26 35409355
2017 Pooled safety analyses of ALK-TKI inhibitor in ALK-positive NSCLC. BMC cancer 26 28606126
2013 Targeted Therapy for Neuroblastoma: ALK Inhibitors. Klinische Padiatrie 26 24166094
2010 Conditional TPM3-ALK and NPM-ALK transgenic mice develop reversible ALK-positive early B-cell lymphoma/leukemia. Blood 26 20223922
2017 Aberrant expression of ALK and EZH2 in Merkel cell carcinoma. BMC cancer 25 28359267
2016 Synergistic activity of ALK and mTOR inhibitors for the treatment of NPM-ALK positive lymphoma. Oncotarget 25 27662658
2020 Emerging Roles of ALK in Immunity and Insights for Immunotherapy. Cancers 24 32059449
2018 CMTR1-ALK: an ALK fusion in a patient with no response to ALK inhibitor crizotinib. Cancer biology & therapy 24 30273505
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
2018 ALK is a critical regulator of the MYC-signaling axis in ALK positive lung cancer. Oncotarget 23 29507657
2017 Managing Resistance to EFGR- and ALK-Targeted Therapies. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting 23 28561721
2012 Detection of anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer and related issues in ALK inhibitor therapy: a literature review. Molecular diagnosis & therapy 23 22506598
2022 HER3 activation contributes toward the emergence of ALK inhibitor-tolerant cells in ALK-rearranged lung cancer with mesenchymal features. NPJ precision oncology 22 35042943
2022 Non-small-cell lung cancer: how to manage ALK-, ROS1- and NTRK-rearranged disease. Drugs in context 22 36303600
2025 ALK in cancer: from function to therapeutic targeting. Nature reviews. Cancer 19 40055571
2021 Brigatinib: A Review in ALK-Inhibitor Naïve Advanced ALK-Positive NSCLC. Drugs 19 33528789
2021 Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma-A Comprehensive Update. Pharmaceutics 18 34575503
2019 Fusion of ALK to the melanophilin gene MLPH in pediatric Spitz nevi. Human pathology 17 30857967
2016 De novo ALK kinase domain mutations are uncommon in kinase inhibitor-naïve ALK rearranged lung cancers. Lung cancer (Amsterdam, Netherlands) 17 27565908
2023 ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition. Proceedings of the National Academy of Sciences of the United States of America 16 38154064

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