Abstract
Despite the benefits of imatinib for treating gastrointestinal stromal tumors (GIST), the prognosis for high risk GIST and imatinib-resistant (IR) GIST remains poor. The mechanisms of imatinib resistance have not yet been fully clarified. The aim of the study was to establish imatinib-resistant cell lines and investigate nilotinib, a second generation tyrosine kinase inhibitor (TKI), in preclinical models of GIST and imatinib-resistant GIST. For a model of imatinib-resistant GIST, we generated resistant cells from GK1C and GK3C cell lines by exposing them to imatinib for 6 months. The parent cell lines GK1C and GK3C showed imatinib sensitivity with IC50 of 4.59±0.97 µM and 11.15±1.48 µM, respectively. The imatinib-resistant cell lines GK1C-IR and GK3C-IR showed imatinib resistance with IC50 values of 11.74±0.17 µM (P<0.001) and 41.37±1.07 µM (P<0.001), respectively. The phosphorylation status of key cell signaling pathways, receptor tyrosine kinase KIT (CD117), platelet-derived growth factor receptor alpha (PDGFRA) and downstream signaling kinases: serine-threonine kinase Akt (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) or the non-receptor tyrosine kinase: proto-oncogene tyrosine-protein kinase Src (SRC), was analyzed in established cell lines and ERK1/2 phosphorylation was found to be increased compared to the parental cells. Nilotinib demonstrated significant antitumor efficacy against GIST xenograft lines and imatinib-resistant GIST cell lines. Thus, nilotinib may have clinical potential for patients with GIST or imatinib-resistant GIST.
Highlights
Gastrointestinal stromal tumor (GIST) is a mesenchymal cell neoplasm with an annual incidence of 10–20 cases per million people
Antitumor effect for GIST xenograft lines To determine whether nilotinib therapy would have benefits that are not inferior to imatinib, we demonstrated the efficacy of antitumor activity in KIT-positive GIST xenograft lines (GK1X, GK2X and GK3X) (Fig. 1A)
Efficacy of nilotinib for imatinib-resistant GIST cell lines We evaluated whether the tyrosine kinase inhibitor nilotinib could inhibit the proliferation of parent GIST cell lines (GK1C and GK3C) and imatinib-resistant GIST cell lines (GK1C-IR and GK3C-IR)
Summary
Gastrointestinal stromal tumor (GIST) is a mesenchymal cell neoplasm with an annual incidence of 10–20 cases per million people. 20 years ago, the interstitial cells of Cajal (ICCs) were first identified as the cell of origin for GIST. Located between the autonomic nerves and the muscle walls of the gastrointestinal tract, ICCs are a population of cells that control peristaltic contractions and are characterized by their expression of the tyrosine kinase receptor KIT (CD117), a receptor for stem cell factor (SCF) [2]. SCF binding to KIT leads to receptor homodimerization and intracellular kinase activation, setting off a signaling cascade that positively regulates both the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)-AKT pathways [3]. The vast majority of GIST are positive for KIT protein expression, and 70–80% of GIST contain activating mutations in KIT, which result in constitutive activation via auto-phosphorylation and SCF-independent signaling and cellular proliferation [4]
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