Cargando…
Antitumor Effect of the Tyrosine Kinase Inhibitor Nilotinib on Gastrointestinal Stromal Tumor (GIST) and Imatinib-Resistant GIST Cells
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...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164645/ https://www.ncbi.nlm.nih.gov/pubmed/25221952 http://dx.doi.org/10.1371/journal.pone.0107613 |
_version_ | 1782334979266576384 |
---|---|
author | Sako, Hiroyuki Fukuda, Kazumasa Saikawa, Yoshiro Nakamura, Rieko Takahashi, Tsunehiro Wada, Norihito Kawakubo, Hirohumi Takeuchi, Hiroya Ohmori, Tai Kitagawa, Yuko |
author_facet | Sako, Hiroyuki Fukuda, Kazumasa Saikawa, Yoshiro Nakamura, Rieko Takahashi, Tsunehiro Wada, Norihito Kawakubo, Hirohumi Takeuchi, Hiroya Ohmori, Tai Kitagawa, Yuko |
author_sort | Sako, Hiroyuki |
collection | PubMed |
description | 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 IC(50) 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 IC(50) 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. |
format | Online Article Text |
id | pubmed-4164645 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-41646452014-09-19 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, Hirohumi Takeuchi, Hiroya Ohmori, Tai Kitagawa, Yuko PLoS One Research Article 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 IC(50) 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 IC(50) 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. Public Library of Science 2014-09-15 /pmc/articles/PMC4164645/ /pubmed/25221952 http://dx.doi.org/10.1371/journal.pone.0107613 Text en © 2014 Sako et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Sako, Hiroyuki Fukuda, Kazumasa Saikawa, Yoshiro Nakamura, Rieko Takahashi, Tsunehiro Wada, Norihito Kawakubo, Hirohumi Takeuchi, Hiroya Ohmori, Tai Kitagawa, Yuko Antitumor Effect of the Tyrosine Kinase Inhibitor Nilotinib on Gastrointestinal Stromal Tumor (GIST) and Imatinib-Resistant GIST Cells |
title | Antitumor Effect of the Tyrosine Kinase Inhibitor Nilotinib on Gastrointestinal Stromal Tumor (GIST) and Imatinib-Resistant GIST Cells |
title_full | Antitumor Effect of the Tyrosine Kinase Inhibitor Nilotinib on Gastrointestinal Stromal Tumor (GIST) and Imatinib-Resistant GIST Cells |
title_fullStr | Antitumor Effect of the Tyrosine Kinase Inhibitor Nilotinib on Gastrointestinal Stromal Tumor (GIST) and Imatinib-Resistant GIST Cells |
title_full_unstemmed | Antitumor Effect of the Tyrosine Kinase Inhibitor Nilotinib on Gastrointestinal Stromal Tumor (GIST) and Imatinib-Resistant GIST Cells |
title_short | Antitumor Effect of the Tyrosine Kinase Inhibitor Nilotinib on Gastrointestinal Stromal Tumor (GIST) and Imatinib-Resistant GIST Cells |
title_sort | antitumor effect of the tyrosine kinase inhibitor nilotinib on gastrointestinal stromal tumor (gist) and imatinib-resistant gist cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164645/ https://www.ncbi.nlm.nih.gov/pubmed/25221952 http://dx.doi.org/10.1371/journal.pone.0107613 |
work_keys_str_mv | AT sakohiroyuki antitumoreffectofthetyrosinekinaseinhibitornilotinibongastrointestinalstromaltumorgistandimatinibresistantgistcells AT fukudakazumasa antitumoreffectofthetyrosinekinaseinhibitornilotinibongastrointestinalstromaltumorgistandimatinibresistantgistcells AT saikawayoshiro antitumoreffectofthetyrosinekinaseinhibitornilotinibongastrointestinalstromaltumorgistandimatinibresistantgistcells AT nakamurarieko antitumoreffectofthetyrosinekinaseinhibitornilotinibongastrointestinalstromaltumorgistandimatinibresistantgistcells AT takahashitsunehiro antitumoreffectofthetyrosinekinaseinhibitornilotinibongastrointestinalstromaltumorgistandimatinibresistantgistcells AT wadanorihito antitumoreffectofthetyrosinekinaseinhibitornilotinibongastrointestinalstromaltumorgistandimatinibresistantgistcells AT kawakubohirohumi antitumoreffectofthetyrosinekinaseinhibitornilotinibongastrointestinalstromaltumorgistandimatinibresistantgistcells AT takeuchihiroya antitumoreffectofthetyrosinekinaseinhibitornilotinibongastrointestinalstromaltumorgistandimatinibresistantgistcells AT ohmoritai antitumoreffectofthetyrosinekinaseinhibitornilotinibongastrointestinalstromaltumorgistandimatinibresistantgistcells AT kitagawayuko antitumoreffectofthetyrosinekinaseinhibitornilotinibongastrointestinalstromaltumorgistandimatinibresistantgistcells |