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In vivo effects of short- and long-term MAPK pathway inhibition against neuroblastoma

Yuki Takeuchi1, Tomoko Tanaka1, Mayumi Higashi1

  • 1Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Journal of Pediatric Surgery
|September 30, 2018
PubMed
Abstract

Insights

MAPK pathway inhibition effectively treated pERK-positive neuroblastoma in vivo, but acquired drug resistance emerged with long-term treatment. pERK immunohistochemistry may serve as a biomarker for neuroblastoma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Relapsed neuroblastomas frequently exhibit mutations in the MAPK pathway.
  • Previous in vitro studies demonstrated antitumor effects of MEK inhibitors (trametinib) and RAF/MEK inhibitors (CH5126766) on neuroblastoma cells with ERK phosphorylation (pERK).

Purpose of the Study:

  • To investigate the in vivo efficacy of MAPK pathway inhibition in neuroblastoma xenografts.
  • To evaluate pERK immunohistochemistry as a potential biomarker for treatment response.

Main Methods:

  • Neuroblastoma xenografts (IMR5, CHP-212, SK-N-AS) were treated daily with trametinib or CH5126766 for short-term (2 weeks) or long-term (8 weeks).
  • Tumor growth was monitored, and post-treatment histopathological analyses included pERK and Ki67 immunohistochemistry.

Main Results:

  • Short-term treatment significantly inhibited tumor growth in pERK-positive CHP-212 and SK-N-AS xenografts, with decreased pERK and Ki67 expression.
  • IMR5 xenografts, negative for pERK, showed resistance to treatment.
  • Long-term treatment led to tumor regrowth in SK-N-AS xenografts around six weeks, characterized by partial differentiation and re-emergence of pERK-positive cells.

Conclusions:

  • MAPK pathway inhibition is an effective in vivo treatment strategy for pERK-positive neuroblastoma.
  • pERK immunohistochemistry shows promise as a biomarker for guiding MAPK pathway inhibition therapy in neuroblastoma.
  • Acquired drug resistance developed after long-term treatment, necessitating further research to overcome this challenge.
Keywords:
Acquired drug resistanceMAPK pathway inhibitionMEK inhibitorNeuroblastomaPartial differentiationpERK IHC

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