Abstract
Tropomyosin receptor kinase (TRK) and receptor tyrosine kinase (RTK class VII) expression are important in many human diseases, especially cancers, including colorectal, lung, and gastric cancer. Using RNA sequencing analysis, we evaluated the mRNA expression and mutation profiles of gastric cancer patients with neurotropic tropomyosin receptor kinase (NTRK) 1-3 overexpression (defined as a ≥2.0-fold change). Furthermore, we screened eight TRK inhibitors in NCI-N87, SNU16, MKN28, MKN7, and AGS cells. Among these inhibitors, entrectinib showed the highest inhibitory activity; therefore, this drug was selected for analysis of its therapeutic mechanisms in gastric cancer. Entrectinib treatment induced apoptosis in NTRK1-3-expressing and VEGFR2-expressing NCI-N87 and AGS cells, but it had no effect on NTRK1-3-, VEGFR2-, TGFBR1-, and CD274-expressing MKN7 cells. SNU16 and MKN28 cells with low NTRK1-3 expression were not affected by entrectinib. Therefore, a mechanistic study was conducted in NCI-N87 (high expression of NTRK1-3 but mutation of NTRK3), AGS (high expression of NTRK1-3) and MKN28 (low expression of NTRK1-3) gastric cancer cell lines. Entrectinib treatment significantly reduced expression levels of phosphorylated NFκB, AKT, ERK, and β-catenin in NCI-N87 and AGS cells, whereas it upregulated the expression levels of ECAD in NCI-N87 cells. Together, these results suggest that entrectinib has anti-cancer activity not only in GC cells overexpressing pan NTRK but also in VEGFR2 GC cells via the inhibition of the pan NTRK and VEGFR signaling pathways.
Highlights
Gastric cancer (GC) is the most prevalent malignant tumor in Korea
We evaluated the effects of entrectinib on apoptosis and epithelial–mesenchymal transition (EMT) in a GC cell line, as well as its potential therapeutic mechanism
NTRK1 was upregulated in nine patients, NTRK2 in nine patients, and NTRK3 in seven patients (Figure 1b)
Summary
Gastric cancer (GC) is the most prevalent malignant tumor in Korea. Metastasis is a major obstacle for improving long-term survival after surgical resection [1]. There is a need to identify effective therapeutic targets for metastatic GC. Neurotropic tropomyosin receptor kinases (NTRK1, NTRK2, and NTRK3) encode tyrosine receptor kinases (TRKA, TRKB, and TRKC), which induce many types of cancer pathogenesis through the activation of downstream signaling [2]. NTRK gene fusions are known to be oncogenic, while NTRK gene amplifications are associated with metastatic cancer [3]. NTRK gene amplification was shown to result in TRK overexpression [3]. For the treatment of NTRK gene fusion, several TRK inhibitors have been developed. NTRK gene rearrangement is rare in cancer, so target therapy is rarely applicable
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