TY - JOUR
T1 - Antitumor effect of the tyrosine kinase inhibitor nilotinib on gastrointestinal stromal tumor (GIST) and imatinib-resistant GIST cells
AU - Sako, Hiroyuki
AU - Fukuda, Kazumasa
AU - Saikawa, Yoshiro
AU - Nakamura, Rieko
AU - Takahashi, Tsunehiro
AU - Wada, Norihito
AU - Kawakubo, Hirohumi
AU - Takeuchi, Hiroya
AU - Ohmori, Tai
AU - Kitagawa, Yuko
N1 - Funding Information:
We thank Novartis, Ltd. for provision of compounds and for helpful discussions. Financial support was provided by Novartis Phama funded research and Grant-in-Aid for Young Scientists (B), The Ministry of Education, Culture, Sports, Science and Technology (MEXT). We are grateful to Yumi Yoshimura for valued technical assistance.
Publisher Copyright:
© 2014 PLOS ONE.
PY - 2014/9/15
Y1 - 2014/9/15
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0107613
DO - 10.1371/journal.pone.0107613
M3 - Article
C2 - 25221952
AN - SCOPUS:84907168788
VL - 9
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 9
M1 - e107613
ER -