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Early and late effects of pharmacological ALK inhibition on the neuroblastoma transcriptome

Shana Claeys1,2, Geertrui Denecker1,2, Robrecht Cannoodt1,2,3,4,5

  • 1Center for Medical Genetics, Ghent University, Ghent, Belgium.

Oncotarget
|January 2, 2018
PubMed
Abstract

Insights

Neuroblastoma treatment with ALK inhibitor TAE684 revealed early changes in gene expression, including unexpected MYCN target gene upregulation and early adrenomedullin (ADM) response. Further research is needed to understand ADM

Area of Science:

  • Pediatric Oncology
  • Molecular Biology
  • Cancer Genomics

Background:

  • Neuroblastoma is a high-risk childhood cancer with poor outcomes for high-risk patients.
  • Activating mutations in ALK offer a target for precision medicine in a subset of neuroblastoma.
  • Novel therapeutic strategies are crucial due to limitations in current multi-modal treatments.

Purpose of the Study:

  • To investigate the dynamic transcriptional changes in neuroblastoma cells following ALK inhibition.
  • To identify early molecular targets for combination therapies.
  • To understand the temporal effects of ALK inhibition on neuroblastoma gene expression.

Main Methods:

  • Analysis of neuroblastoma cell line transcriptomes at detailed time points (10 minutes to 6 hours) after TAE684 treatment.
  • Investigated dynamic gene expression profiles to understand molecular effects of ALK signaling.
  • Utilized a 77-gene ALK signature to track transcriptional effects.

Main Results:

  • Observed initial upregulation of MYCN target genes despite overall MYCN activity decrease.
  • Identified adrenomedullin (ADM) as the earliest response gene to ALK inhibition.
  • Characterized early and late transcriptional effects of TAE684 on neuroblastoma.

Conclusions:

  • ALK inhibitor TAE684 treatment induces distinct early and late transcriptional changes in neuroblastoma.
  • The early upregulation of ADM suggests a potential role in ALK inhibitor resistance.
  • Further investigation of ADM is warranted for neuroblastoma patients receiving ALK inhibitor therapy.
Keywords:
ALKALK inhibitionALK signalingdynamicneuroblastoma

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