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

Hiroyuki Sako, Kazumasa Fukuda, Yoshiro Saikawa, Rieko Nakamura, Tsunehiro Takahashi, Norihito Wada, Hirofumi Kawakubo, Hiroya Takeuchi, Tai Ohmori, Yuukou Kitagawa

Research output: Contribution to journalArticle

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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 IC50of 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 IC50values 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.

Original languageEnglish
Article numbere107613
JournalPLoS One
Volume9
Issue number9
DOIs
Publication statusPublished - 2014 Sep 15

Fingerprint

Gastrointestinal Stromal Tumors
stromal cells
Stromal Cells
Protein-Tyrosine Kinases
tyrosine
Tumors
phosphotransferases (kinases)
neoplasms
cell lines
Cells
Cell Line
mitogen-activated protein kinase
phosphorylation
Phosphorylation
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
proto-oncogenes
neoplasm cells
Imatinib Mesylate
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Antitumor effect of the tyrosine kinase inhibitor nilotinib on gastrointestinal stromal tumor (GIST) and imatinib-resistant GIST cells. / Sako, Hiroyuki; Fukuda, Kazumasa; Saikawa, Yoshiro; Nakamura, Rieko; Takahashi, Tsunehiro; Wada, Norihito; Kawakubo, Hirofumi; Takeuchi, Hiroya; Ohmori, Tai; Kitagawa, Yuukou.

In: PLoS One, Vol. 9, No. 9, e107613, 15.09.2014.

Research output: Contribution to journalArticle

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