AI Article Synopsis
- Pediatric gastroenteropancreatic neuroendocrine tumors are rare, leading to treatments often based on adult data, and trametinib, a MEK1/2 inhibitor, has been used for tumors with Ras pathway mutations.
- Research on a patient-derived xenograft with an NRAS mutation showed that trametinib effectively reduced tumor growth, cell motility, and improved survival in laboratory mice.
- The findings suggest that further studies on MEK inhibition could be beneficial for treating pediatric tumors with NRAS mutations.
Article Abstract
Background: Pediatric gastroenteropancreatic neuroendocrine tumors are exceedingly rare, resulting in most pediatric treatment recommendations being based on data derived from adults. Trametinib is a kinase inhibitor that targets MEK1/2 and has been employed in the treatment of cancers harboring mutations in the Ras pathway.
Methods: We utilized an established human pediatric gastroenteropancreatic neuroendocrine-like tumor patient-derived xenograft (PDX) with a known NRAS mutation to study the effects of MEK inhibition. We evaluated the effects of trametinib on proliferation, motility, and tumor growth in vivo. We created an intraperitoneal metastatic model of this PDX, characterized both the phenotype and the genotype of the metastatic PDX and again, investigated the effects of MEK inhibition.
Results: We found target engagement with decreased ERK1/2 phosphorylation with trametinib treatment. Trametinib led to decreased in vitro cell growth and motility, and decreased tumor growth and increased animal survival in a murine flank tumor model. Finally, we demonstrated that trametinib was able to significantly decrease gastroenteropancreatic neuroendocrine intraperitoneal tumor metastasis.
Conclusions: The results of these studies support the further investigation of MEK inhibition in pediatric NRAS mutated solid tumors.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11269785 | PMC |
| http://dx.doi.org/10.1016/j.tranon.2024.102045 | DOI Listing |
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