In vivo effects of short- and long-term MAPK pathway inhibition against neuroblastoma
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In brief
In brief
Study demonstrates MEK and RAF/MEK inhibitors effectively suppress growth in pERK-positive neuroblastoma xenografts short-term, with pERK status serving as potential treatment biomarker. However, tumors develop acquired resistance during prolonged treatment, with pERK reactivation observed after six weeks, highlighting need for combination strategies.
Written by the GCMD Library team from the article.
Background/purpose
It was reported that almost 80% of relapsed neuroblastomas showed MAPK pathway mutations. In our previous study, both trametinib (MEK inhibitor) and CH5126766 (RAF/MEK inhibitor) showed in vitro antitumor effects on neuroblastoma cells with ERK phosphorylation (pERK). In this study, we analyzed the in vivo effects of MAPK pathway inhibition in neuroblastoma xenografts.
Methods
Xenograft mice with IMR5, CHP-212, or SK-N-AS received daily oral administration of either trametinib or CH5126766 for two weeks (short term) or eight weeks (long term). The tumors were measured twice weekly and harvested after treatment for histopathological analyses, including pERK and Ki67 immunohistochemistry.
Results
In short-term treatment, both inhibitors showed significant growth inhibition in CHP-212 and SK-N-AS xenografts, which were pERK-positive before treatment. The number of pERK- and Ki67-positive cells decreased after treatment. Conversely, IMR5 xenografts, which were pERK-negative, were resistant to treatment. During long-term treatment, SK-N-AS xenografts started to regrow from about six weeks with partial differentiation. pERK-positive cells reincreased in these regrown tumors.
Conclusions
MAPK pathway inhibition was effective for treating pERK-positive neuroblastoma in vivo. Therefore, pERK immunohistochemistry might be a convenient biomarker for MAPK pathway inhibition in neuroblastoma treatment. However, neuroblastomas developed acquired drug resistance after long-term treatment. Further studies to overcome acquired resistance are needed.