ArticleNeuro-oncology2017
Tyrosine receptor kinase B is a drug target in astrocytomas.
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Article in Neuro-oncology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 40 citations in OpenAlex.
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- Receptor Tyrosine Kinase Signaling and Targeting in Glioblastoma Multiforme.International journal of molecular sciences · 2021Review
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- Neurotrophin Signaling in Medulloblastoma.Cancers · 2020Review
- Molecular and clinicopathologic features of gliomas harboring NTRK fusions.Acta neuropathologica communications · 2020Article
- A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways.Nature communications · 2020Article
- NTRK Fusions and TRK Inhibitors: Potential Targeted Therapies for Adult Glioblastoma.Frontiers in oncology · 2020Review
- Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy.The Journal of molecular diagnostics : JMD · 2019Review
- Therapeutic Interventions in Adult Low-Grade Gliomas.Journal of clinical neurology (Seoul, Korea) · 2019Review
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- TRK Inhibition: A New Tumor-Agnostic Treatment Strategy.Targeted oncology · 2018Review
- Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression.Cell stem cell · 2018Article
- Pediatric low-grade gliomas: next biologically driven steps.Neuro-oncology · 2018Review
- Inhibitor repurposing reveals ALK, LTK, FGFR, RET and TRK kinases as the targets of AZD1480.Oncotarget · 2017Article
- Targeting tyrosine receptor kinase B in gliomas.Neuro-oncology · 2017Article
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Authors and funding
13 authors at 5 institutions in 1 country.
Jing NiDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.).
Shaozhen XieDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.).
Shakti H RamkissoonDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.).
Victor LuuDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.).
Yu SunDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.).
Pratiti BandopadhayayDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.).
Rameen BeroukhimDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.).
Thomas M RobertsDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.).
Charles D StilesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.).
Rosalind A SegalDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.).
Keith L LigonDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.).
William C HahnDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.).
Jean J ZhaoDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.) jean_zhao@dfci.harvard.edu.
Boston Children's Hospital · USBrigham and Women's Hospital · USBroad Institute · USHarvard University · USDana-Farber Cancer Institute · US
Funding
Targeting the Vasular SystemP50CA165962 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Benjamin Harris Kann · 2013 to 2026
$33.5MPROJECT 4: Interrogating PP2A Signaling in Human CancersP01CA203655 · NCI · DANA-FARBER CANCER INST · PI DECAPRIO, JAMES A. · 2017 to 2021
$8.0MTherapeutic Opportunities for Pediatric AstrocytomaP01CA142536 · NCI · DANA-FARBER CANCER INST · PI SEGAL, ROSALIND A. · 2011 to 2015
$7.9MNCI NIH HHS P01 CA142536NCI NIH HHS P01 CA203655NCI NIH HHS P50 CA165962
Abstract
backgroundAstrocytomas are the most common primary human brain tumors. Receptor tyrosine kinases (RTKs), including tyrosine receptor kinase B (TrkB, also known as tropomyosin-related kinase B; encoded by neurotrophic tyrosine kinase receptor type 2 [NTRK2]), are frequently mutated by rearrangement/fusion in high-grade and low-grade astrocytomas. We found that activated TrkB can contribute to the development of astrocytoma and might serve as a therapeutic target in this tumor type.
methodsTo identify RTKs capable of inducing astrocytoma formation, a library of human tyrosine kinases was screened for the ability to transform murine Ink4a
resultsActivated TrkB cooperated with Ink4a/Arf loss to induce the formation of astrocytomas through a mechanism mediated by activation of signal transducer and activator of transcription 3 (STAT3). TrkB activation positively correlated with Ccl2 expression. TrkB-induced astrocytomas remained dependent on TrkB signaling for survival, highlighting a role of NTRK2 as an addictive oncogene. Furthermore, the QKI-NTRK2 fusion associated with human astrocytoma transformed Ink4a
conclusionsOur findings provide evidence that constitutively activated NTRK2 alleles, notably the human tumor-associated QKI-NTRK2 fusion, can cooperate with Ink4a/Arf loss to drive astrocytoma formation. Therefore, we propose NTRK2 as a potential therapeutic target in the subset of astrocytoma patients defined by QKI-NTRK2 fusion.
Indexed as
ADP-Ribosylation Factor 1AnimalsAstrocytesAstrocytomaCells, CulturedCyclin-Dependent Kinase Inhibitor p16High-Throughput Screening AssaysHumansMembrane GlycoproteinsMiceMice, KnockoutOncogene Proteins, FusionReceptor, trkBRNA-Binding ProteinsSignal TransductionADP-Ribosylation Factor 1Cyclin-Dependent Kinase Inhibitor p16Membrane GlycoproteinsOncogene Proteins, FusionQKI protein, humanReceptor, trkBRNA-Binding Proteinstropomyosin-related kinase-B, humanastrocytomaCCL2NTRK2QKI-NTRK2STAT3
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