Tropomyosin receptor kinase: a novel target in screened neuroendocrine tumors

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Tropomyosin receptor kinase (Trk) inhibitors represent a novel targeted therapy approach for various cancers.
• Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies with diverse treatment options.

Purpose of the Study:

• To investigate the in vitro anti-tumoral effects of the pan-Trk inhibitor GNF-5837 in human neuroendocrine tumor (NET) cell lines.
• To evaluate the efficacy of GNF-5837 alone and in combination with everolimus.
• To determine the role of Trk receptor expression in GNF-5837 sensitivity.

Main Methods:

• In vitro treatment of human NET cell lines (BON1, NCI-H727, GOT1) with GNF-5837 and everolimus.
• Assessment of cell viability, signaling pathway modulation (PI3K-Akt-mTOR, Ras-Raf-MEK-ERK), cell cycle, and apoptosis.
• Immunohistochemical staining for TrkA and pan-Trk receptors in 107 gastroenteropancreatic NET samples.

Main Results:

• GNF-5837 decreased cell viability in GOT1 cells in a time- and dose-dependent manner, but not in BON1 or NCI-H727 cells.
• Trk receptor expression levels correlated with GNF-5837 sensitivity.
• GNF-5837 treatment led to downregulation of key signaling pathways, cell cycle arrest, and increased apoptosis.
• Combination therapy with everolimus significantly enhanced the inhibition of cell viability through cooperative pathway downregulation.
• Positive TrkA and pan-Trk receptor staining was observed in 24.2% and 33.3% of pancreatic NETs, respectively.

Conclusions:

• The pan-Trk inhibitor GNF-5837 demonstrates promising anti-tumoral activity in TrkA-expressing human NET cell lines.
• Combined treatment with GNF-5837 and everolimus exhibits synergistic anti-cancer effects in NET cells.
• Trk receptor expression, particularly in pancreatic NETs, may serve as a predictive biomarker for response to Trk inhibitor therapy.