Antitumor effect of the tyrosine kinase inhibitor nilotinib on gastrointestinal stromal tumor (GIST) and imatinib-resistant GIST cells

• Published in: PloS one Vol. 9; no. 9; p. e107613
• Main Authors: Sako, Hiroyuki, Fukuda, Kazumasa, Saikawa, Yoshiro, Nakamura, Rieko, Takahashi, Tsunehiro, Wada, Norihito, Kawakubo, Hirohumi, Takeuchi, Hiroya, Ohmori, Tai, Kitagawa, Yuko
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.09.2014; Public Library of Science (PLoS)
• Subjects: AKT protein; Analysis; Animals; Anticancer properties; Antitumor activity; Apoptosis; Biotechnology; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Cellular signal transduction; Drug dosages; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Enzyme inhibitors; Extracellular signal-regulated kinase; Gastrointestinal cancer; Gastrointestinal Stromal Tumors - drug therapy; Gastrointestinal Stromal Tumors - genetics; Humans; Imatinib; Imatinib Mesylate - administration & dosage; Inhibitors; Kinases; Laboratory animals; Medicine; Medicine and Health Sciences; Mice; Mutation; Neoplasm Proteins - metabolism; Oncology; Phenols (Class of compounds); Phosphorylation; Phosphorylation - drug effects; Phosphotransferases; Platelet-derived growth factor; Prognosis; Protein Kinase Inhibitors - administration & dosage; Protein-serine/threonine kinase; Protein-tyrosine kinase receptors; Proto-Oncogene Mas; Pyrimidines - administration & dosage; Signal Transduction - drug effects; Signaling; Src protein; Stem cells; Studies; Surgery; Threonine; Tumors; Tyrosine; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0107613

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.