 |
English
|
正體中文
|
简体中文
|
Items with full text/Total items : 12145/12927 (94%)
Visitors : 860945
Online Users : 962
|
|
|
Loading...
|
Please use this identifier to cite or link to this item:
http://ir.nhri.org.tw/handle/3990099045/5069
|
| Title: | Differential response of primary or secondary exon 13/14 and exon 17 c-kit mutant to nilotinib and sunitinib: Findings from a cell-based drug-screening platform |
| Authors: | Chan, C;Chen, L;Hsueh, Y;Chuang, W;Lee, H;Huang, M;Heieh, R;Weng, W |
| Contributors: | National Institute of Cancer Research |
| Abstract: | ackground: Gastrointestinal stromal tumors (GIST) are frequently associated with mutation of c-kit oncogene that is accompanied with constitutional activation of c-kit protein. At present, imatinib is the drug of choice for unresectable or metastatic GIST, however, primary or acquired resistance to imatinib is frequently associated with the presence of an exon 13, 14 or 17 c-kit mutation. The current recommendations for GIST refractory to standard (400 mg/day) imatinib treatment include increasing dose of imatinib to 600–800 mg/day for tumors with primary exon 9 mutation or sunitinib. Several molecular targeted agents are also under investigation. With so many potential agents, personalized therapy based on c-kit mutant genotype for imatinib-resistant GIST deserves to explore. Methods: We prepared a series of c-kit cDNA constructs encoding mutant exon 9 (502AY insertion), 11 (V560D substitution and {Delta}555–576 deletion), 13 (V654A substitution), 14 (T670I substitution) and 17 (D820G and N822K substitutions) either alone or in combination to simulating the frequently occurred primary ± secondary c-kit mutants in GIST. We expressed these constructs in COS-1 cells to study the efficacy of different tyrosine kinase inhibitors (TKIs) on the autophosphorylation of various single or double mutant c- kit. Results: The efficacy of imatinib on single c-kit mutant was V560D > {Delta}555–576 > 502AY > D820G or N822K, and ineffective for single and double mutants containing V654A or T670I. Sunitinib is a more potent inhibitor for single 502AY, D820G and N822K mutant than imatinib and nilotinib; while single V654A and T670I c-kit mutant are more sensitive to nilotinib. Interestingly, double exon 11 (V560D or {Delta}555–576)/V654A or T670I mutant c-kit are more sensitive to sunitinib; while exon 11 (V560D or {Delta}555–576)/D820G or N822K double mutant c-kit are more sensitive to nilotinib. Conclusions: Our system provides a useful platform to select/screen effective TKIs for GIST with single or double mutant c-kit. The findings of differential response of c-kit mutant to nilotinib and sunitinib may help to select therapy for GIST with primary or secondary exon 13 / 14 and exon 17 mutations. |
| Date: | 2009-05-20 |
| Relation: | Journal of Clinical Oncology. 2009 May 20;27(15):Abstract number e15636. |
| Link to: | http://meeting.ascopubs.org/cgi/content/abstract/27/15S/e15636 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0732-183X&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000276606603352 |
| Appears in Collections: | [陳立宗] 會議論文/會議摘要
|
Files in This Item:
There are no files associated with this item.
|
All items in NHRI are protected by copyright, with all rights reserved.
|
