LMTK3 Is Essential for Oncogenic KIT Expression in KIT-mutant GIST and Melanoma

Oncogene. 2019 Feb;38(8):1200-1210. doi: 10.1038/s41388-018-0508-5. Epub 2018 Sep 21.

Abstract

Certain cancers, including gastrointestinal stromal tumor (GIST) and subsets of melanoma, are caused by somatic KIT mutations that result in KIT receptor tyrosine kinase constitutive activity, which drives proliferation. The treatment of KIT-mutant GIST has been revolutionized with the advent of KIT-directed cancer therapies. KIT tyrosine kinase inhibitors (TKI) are superior to conventional chemotherapy in their ability to control advanced KIT-mutant disease. However, these therapies have a limited duration of activity due to drug-resistant secondary KIT mutations that arise (or that are selected for) during KIT TKI treatment. To overcome the problem of KIT TKI resistance, we sought to identify novel therapeutic targets in KIT-mutant GIST and melanoma cells using a human tyrosine kinome siRNA screen. From this screen, we identified lemur tyrosine kinase 3 (LMTK3) and herein describe its role as a novel KIT regulator in KIT-mutant GIST and melanoma cells. We find that LMTK3 regulated the translation rate of KIT, such that loss of LMTK3 reduced total KIT, and thus KIT downstream signaling in cancer cells. Silencing of LMTK3 decreased cell viability and increased cell death in KIT-dependent, but not KIT-independent GIST and melanoma cell lines. Notably, LMTK3 silencing reduced viability of all KIT-mutant cell lines tested, even those with drug-resistant KIT secondary mutations. Furthermore, targeting of LMTK3 with siRNA delayed KIT-dependent GIST growth in a xenograft model. Our data suggest the potential of LMTK3 as a target for treatment of patients with KIT-mutant cancer, particularly after failure of KIT TKIs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • Gastrointestinal Stromal Tumors / drug therapy*
  • Gastrointestinal Stromal Tumors / genetics
  • Gastrointestinal Stromal Tumors / pathology
  • Humans
  • Imatinib Mesylate / administration & dosage
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / pathology
  • Membrane Proteins / genetics*
  • Mice
  • Mutation / drug effects
  • Protein Kinase Inhibitors / administration & dosage
  • Protein-Serine-Threonine Kinases / genetics*
  • Proto-Oncogene Proteins c-kit / antagonists & inhibitors
  • Proto-Oncogene Proteins c-kit / genetics*
  • RNA, Small Interfering / genetics
  • Xenograft Model Antitumor Assays

Substances

  • Membrane Proteins
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Imatinib Mesylate
  • KIT protein, human
  • Proto-Oncogene Proteins c-kit
  • LMTK3 protein, human
  • Protein-Serine-Threonine Kinases