NTRK3 kinase fusions in Spitz tumours

J Pathol. 2016 Nov;240(3):282-290. doi: 10.1002/path.4775.

Abstract

Oncogenic fusions in TRK family receptor tyrosine kinases have been identified in several cancers and can serve as therapeutic targets. We identified ETV6-NTRK3, MYO5A-NTRK3 and MYH9-NTRK3 fusions in Spitz tumours, and demonstrated that NTRK3 fusions constitutively activate the mitogen-activated protein kinase, phosphoinositide 3-kinase and phospholipase Cγ1 pathways in melanocytes. This signalling was inhibited by DS-6051a, a small-molecule inhibitor of NTRK1/2/3 and ROS1. NTRK3 fusions expand the range of oncogenic kinase fusions in melanocytic neoplasms and offer targets for a small subset of melanomas for which no targeted options currently exist. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: NTRK3 fusion; Spitz naevus; Spitz tumour; atypical Spitz tumour; genetics; kinase inhibitor; melanoma; oncogene; spitzoid melanoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child
  • Child, Preschool
  • Comparative Genomic Hybridization
  • Discoidin Domain Receptor 2 / genetics*
  • Discoidin Domain Receptor 2 / metabolism
  • Female
  • Humans
  • Male
  • Melanoma / enzymology
  • Melanoma / genetics
  • Melanoma / pathology
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Motor Proteins / genetics*
  • Molecular Motor Proteins / metabolism
  • Myosin Heavy Chains / genetics*
  • Myosin Heavy Chains / metabolism
  • Myosin Type V / genetics*
  • Myosin Type V / metabolism
  • Nevus, Epithelioid and Spindle Cell / enzymology*
  • Nevus, Epithelioid and Spindle Cell / genetics
  • Nevus, Epithelioid and Spindle Cell / pathology
  • Oncogene Fusion
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-ets / genetics*
  • Proto-Oncogene Proteins c-ets / metabolism
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Sequence Analysis, DNA
  • Sequence Analysis, RNA
  • Skin Neoplasms / enzymology*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology

Substances

  • ETS translocation variant 6 protein
  • MYH9 protein, human
  • Molecular Motor Proteins
  • Proto-Oncogene Proteins c-ets
  • Repressor Proteins
  • MYO5A protein, human
  • Phosphatidylinositol 3-Kinases
  • DDR2 protein, human
  • Discoidin Domain Receptor 2
  • Mitogen-Activated Protein Kinases
  • Myosin Type V
  • Myosin Heavy Chains