Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors
<p>Abstract</p> <p>Background</p> <p>Activating mutations in Kit receptor tyrosine kinase or the related platelet-derived growth factor receptor (PDGFR) play an important role in the pathogenesis of gastrointestinal stromal tumors (GIST).</p> <p>Methods</...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2010-07-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Online Access: | http://www.jeccr.com/content/29/1/96 |
| _version_ | 1818154307753607168 |
|---|---|
| author | Tasker Andrew S Manoukian Raffi Juan Todd Baron Will Bush Tammy L Baher Angelo Renshaw-Gegg Lisa Caenepeel Sean Polverino Anthony Hughes Paul E |
| author_facet | Tasker Andrew S Manoukian Raffi Juan Todd Baron Will Bush Tammy L Baher Angelo Renshaw-Gegg Lisa Caenepeel Sean Polverino Anthony Hughes Paul E |
| author_sort | Tasker Andrew S |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Activating mutations in Kit receptor tyrosine kinase or the related platelet-derived growth factor receptor (PDGFR) play an important role in the pathogenesis of gastrointestinal stromal tumors (GIST).</p> <p>Methods</p> <p>This study investigated the activity of motesanib, an inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3; PDGFR; and Kit, against primary activating Kit mutants and mutants associated with secondary resistance to imatinib. Single- and double-mutant isoforms of Kit were evaluated for their sensitivity to motesanib or imatinib in autophosphorylation assays and in Ba/F3 cell proliferation assays.</p> <p>Results</p> <p>Motesanib inhibited Kit autophosphorylation in CHO cell lines expressing primary activating mutations in exon 9 (AYins503-504, IC<sub>50 </sub>= 18 nM) and exon 11 (V560 D, IC<sub>50 </sub>= 5 nM; Δ552-559, IC<sub>50 </sub>= 1 nM). Motesanib also demonstrated activity against kinase domain mutations conferring imatinib resistance (V560D/V654A, IC<sub>50 </sub>= 77 nM; V560D/T670I, IC<sub>50 </sub>= 277 nM; Y823 D, IC<sub>50 </sub>= 64 nM) but failed to inhibit the imatinib-resistant D816V mutant (IC<sub>50 </sub>> 3000 nM). Motesanib suppressed the proliferation of Ba/F3 cells expressing Kit mutants with IC<sub>50 </sub>values in good agreement with those observed in the autophosphorylation assays.</p> <p>Conclusions</p> <p>In conclusion, our data suggest that motesanib possesses inhibitory activity against primary Kit mutations and some imatinib-resistant secondary mutations.</p> |
| first_indexed | 2024-12-11T14:24:26Z |
| format | Article |
| id | doaj.art-894c48c767dd436da50963f26a3004d7 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-11T14:24:26Z |
| publishDate | 2010-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-894c48c767dd436da50963f26a3004d72022-12-22T01:02:45ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662010-07-012919610.1186/1756-9966-29-96Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumorsTasker Andrew SManoukian RaffiJuan ToddBaron WillBush Tammy LBaher AngeloRenshaw-Gegg LisaCaenepeel SeanPolverino AnthonyHughes Paul E<p>Abstract</p> <p>Background</p> <p>Activating mutations in Kit receptor tyrosine kinase or the related platelet-derived growth factor receptor (PDGFR) play an important role in the pathogenesis of gastrointestinal stromal tumors (GIST).</p> <p>Methods</p> <p>This study investigated the activity of motesanib, an inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3; PDGFR; and Kit, against primary activating Kit mutants and mutants associated with secondary resistance to imatinib. Single- and double-mutant isoforms of Kit were evaluated for their sensitivity to motesanib or imatinib in autophosphorylation assays and in Ba/F3 cell proliferation assays.</p> <p>Results</p> <p>Motesanib inhibited Kit autophosphorylation in CHO cell lines expressing primary activating mutations in exon 9 (AYins503-504, IC<sub>50 </sub>= 18 nM) and exon 11 (V560 D, IC<sub>50 </sub>= 5 nM; Δ552-559, IC<sub>50 </sub>= 1 nM). Motesanib also demonstrated activity against kinase domain mutations conferring imatinib resistance (V560D/V654A, IC<sub>50 </sub>= 77 nM; V560D/T670I, IC<sub>50 </sub>= 277 nM; Y823 D, IC<sub>50 </sub>= 64 nM) but failed to inhibit the imatinib-resistant D816V mutant (IC<sub>50 </sub>> 3000 nM). Motesanib suppressed the proliferation of Ba/F3 cells expressing Kit mutants with IC<sub>50 </sub>values in good agreement with those observed in the autophosphorylation assays.</p> <p>Conclusions</p> <p>In conclusion, our data suggest that motesanib possesses inhibitory activity against primary Kit mutations and some imatinib-resistant secondary mutations.</p>http://www.jeccr.com/content/29/1/96 |
| spellingShingle | Tasker Andrew S Manoukian Raffi Juan Todd Baron Will Bush Tammy L Baher Angelo Renshaw-Gegg Lisa Caenepeel Sean Polverino Anthony Hughes Paul E Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors Journal of Experimental & Clinical Cancer Research |
| title | Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors |
| title_full | Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors |
| title_fullStr | Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors |
| title_full_unstemmed | Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors |
| title_short | Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors |
| title_sort | motesanib inhibits kit mutations associated with gastrointestinal stromal tumors |
| url | http://www.jeccr.com/content/29/1/96 |
| work_keys_str_mv | AT taskerandrews motesanibinhibitskitmutationsassociatedwithgastrointestinalstromaltumors AT manoukianraffi motesanibinhibitskitmutationsassociatedwithgastrointestinalstromaltumors AT juantodd motesanibinhibitskitmutationsassociatedwithgastrointestinalstromaltumors AT baronwill motesanibinhibitskitmutationsassociatedwithgastrointestinalstromaltumors AT bushtammyl motesanibinhibitskitmutationsassociatedwithgastrointestinalstromaltumors AT baherangelo motesanibinhibitskitmutationsassociatedwithgastrointestinalstromaltumors AT renshawgegglisa motesanibinhibitskitmutationsassociatedwithgastrointestinalstromaltumors AT caenepeelsean motesanibinhibitskitmutationsassociatedwithgastrointestinalstromaltumors AT polverinoanthony motesanibinhibitskitmutationsassociatedwithgastrointestinalstromaltumors AT hughespaule motesanibinhibitskitmutationsassociatedwithgastrointestinalstromaltumors |