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Ref Type Journal Article
PMID (38959709)
Authors Quinn CH, Beierle AM, Williams AP, Marayati R, Bownes LV, Market HR, Erwin ME, Aye JM, Stewart JE, Mroczek-Musulman E, Yoon KJ, Beierle EA
Title Preclinical evidence for employing MEK inhibition in NRAS mutated pediatric gastroenteropancreatic neuroendocrine-like tumors.
Journal Vol Issue Date Pages Journal Short Title
Translational oncology 47 2024 Jul 02 102045 Transl Oncol
URL
Abstract Text 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.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.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.The results of these studies support the further investigation of MEK inhibition in pediatric NRAS mutated solid tumors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS Q61R gastrointestinal neuroendocrine tumor sensitive Trametinib Preclinical - Cell line xenograft Actionable In a preclinical study, Mekinist (trametinib) inhibited viability, proliferation, and migration of a cell line derived from a pediatric gastroenteropancreatic neuroendocrine-like tumor patient-derived xenograft (PDX) model harboring NRAS Q61R in culture and inhibited tumor growth and increased survival compared to treatment with vehicle in a patient-derived xenograft (PDX) cell line model (PMID: 38959709). 38959709