Loading...
|
Please use this identifier to cite or link to this item:
http://ir.nhri.org.tw/handle/3990099045/5547
|
| Title: | Nilotinib and sorafenib are more potent inhibitors for exon 11/17 C-kit mutants than sunitinib: results of incorporating cell-based screening platform and virtual molecular modeling study |
| Authors: | Hsueh, Y;Lin, C;Chen, T;Ko, C;Shih, N;Wang, L;Chen, L |
| Contributors: | National Institute of Cancer Research |
| Abstract: | Gastrointestinal stromal tumors (GISTs) are frequently associated with the constitutiveactivation mutation of c-Kit receptor tyrosine kinase. Imatinib (gleevec ), a multi-tyrosine kinases inhibitor (TKI), is the current first-line therapy for metastatic or unresectable GIST. Among those initially responsive tumors, 50% will develop imatinib-resistant clone(s) within 2 years of therapy, frequently associated with acquired, secondary c-Kit mutations at exon 13, 14, or 17. Our laboratory has constructed a series of c-Kit mutants, including exon 9, 11, 13, 14, and 17 either alone or in combination, to simulating the frequently occurred c-Kit mutants. These constructs were expressed to study the suppression efficacy of TKIs on the phosphorylation status of c-Kit proteins. We further investigated the molecular structure interaction of the exon 11/17 and exon 11/13 or 14 mutants c-Kit to various TKIs by virtual modeling. Subsequent studies showed that the each TKI preferentially inhibited the activation of different double mutant c-Kit. Sunitinib more strongly inhibits the phosphorylation of exon 11/13 or 14 c-Kit mutants than those with exon 11/17 mutations. In contrast, nilotinib and sorafenib preferentially inhibited the activation of exon 11/17 c-Kit mutants. Virtual modeling showed that the point mutation on exon 14 formed the steric hindrance to block the binding of TKI to c-Kit. The deletion of exon 11 and point mutation on exon 17 would lead to the instability of auto-inhibited c-Kit, shifting conformational equilibrium from the inactive toward the active form. Binding energy suggested that nilotinib and sorafenib could more stably bind to exon 11/17 than imatinib and sunitinib. Mutations on exon11/13 or 14 drive c-Kit conformation to intermediate form, which sunitinib showed better binding affinity than the others. In brief, we have established an in vitro cell-based platform for c-Kit TKIs screening and clari?ed the efficacies of known TKIs to imatinib-resistant c-Kit mutations. The virtual modeling provides explanations for different TKIs sensitivity to various primary ± secondary c-Kit mutants. |
| Date: | 2010-10 |
| Relation: | Annals of Oncology. 2010 Oct;21(Suppl. 8):56-56. |
| Link to: | http://dx.doi.org/10.1093/annonc/mdq513 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0923-7534&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000283115900151 |
| Appears in Collections: | [陳立宗] 會議論文/會議摘要
[施能耀] 會議論文/會議摘要
|
Files in This Item:
| File |
Description |
Size | Format | |
|---|
| ISI000283115900151.pdf | | 333Kb | Adobe PDF | 829 | View/Open |
|
All items in NHRI are protected by copyright, with all rights reserved.
|
