Tyrosine receptor kinase B is a drug target in astrocytomas

Neuro Oncol. 2017 Jan;19(1):22-30. doi: 10.1093/neuonc/now139. Epub 2016 Jul 10.


Background: Astrocytomas 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.

Methods: To identify RTKs capable of inducing astrocytoma formation, a library of human tyrosine kinases was screened for the ability to transform murine Ink4a-/-/Arf-/- astrocytes. Orthotopic allograft studies were conducted to evaluate the effects of RTKs on the development of astrocytoma. Since TrkB was identified as a driver of astrocytoma formation, the effect of the Trk inhibitors AZD1480 and RXDX-101 was assessed in astrocytoma cells expressing activated TrkB. RNA sequencing, real-time PCR, western blotting, and enzyme-linked immunosorbent assays were conducted to characterize NTRK2 in astrocytomas.

Results: Activated 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-/-/Arf-/- astrocytes, and this process was also mediated via STAT3 signaling.

Conclusions: Our 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.

Keywords: NTRK2; CCL2; QKI-NTRK2; STAT3; astrocytoma.

Publication types

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

MeSH terms

  • ADP-Ribosylation Factor 1 / physiology*
  • Animals
  • Astrocytes / enzymology
  • Astrocytes / pathology*
  • Astrocytoma / enzymology
  • Astrocytoma / pathology*
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p16 / physiology
  • High-Throughput Screening Assays
  • Humans
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • Oncogene Proteins, Fusion / metabolism*
  • RNA-Binding Proteins / metabolism*
  • Receptor, trkB / metabolism*
  • Signal Transduction


  • Cyclin-Dependent Kinase Inhibitor p16
  • Membrane Glycoproteins
  • Oncogene Proteins, Fusion
  • QKI protein, human
  • RNA-Binding Proteins
  • Receptor, trkB
  • tropomyosin-related kinase-B, human
  • ADP-Ribosylation Factor 1