Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants
Article first published online: 4 JAN 2014
© 2013 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japan Cancer Association.
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Volume 105, Issue 1, pages 117–125, January 2014
How to Cite
Cancer Sci 105 (2014) 117–125
- Issue published online: 24 JAN 2014
- Article first published online: 4 JAN 2014
- Accepted manuscript online: 10 NOV 2013 10:17PM EST
- Manuscript Accepted: 5 NOV 2013
- Manuscript Revised: 22 OCT 2013
- Manuscript Received: 21 AUG 2013
- National Natural Science Foundation of China. Grant Numbers: Y201181042, 81273546
- National Science and Technology Major Project. Grant Numbers: 2013ZX09102008, 2013ZX09402102-001-004
- Drug resistance;
- gastrointestinal stromal tumors;
- imatinib mesylate;
- sunitinib malate
Activating mutations in KIT have been associated with gastrointestinal stromal tumors (GISTs). The tyrosine kinase inhibitor imatinib mesylate has revolutionized the treatment of GISTs. Unfortunately, primary or acquired resistance to imatinib does occur in GISTs and forms a major problem. Although sunitinib malate, a multi-kinase inhibitor, has shown effectiveness against imatinib-resistant GISTs, recent studies have indicated that some imatinib-resistant GISTs harboring secondary mutations in the KIT activation loop were also resistant to sunitinib. Therefore, new drugs capable of overcoming the dual drug resistance of GISTs probably have potential clinical utility. In this study, we investigated the efficacy of flumatinib, an inhibitor of BCR-ABL/PDGFR/KIT, against 32D cells transformed by various KIT mutants and evaluated its potency to overcome the drug resistance of certain mutants. Interestingly, our in vitro study revealed that flumatinib effectively overcame the drug resistance of certain KIT mutants with activation loop mutations (i.e., D820G, N822K, Y823D, and A829P). Our in vivo study consistently suggested that flumatinib had superior efficacy compared with imatinib or sunitinib against 32D cells with the secondary mutation Y823D. Molecular modeling of flumatinib docked to the KIT kinase domain suggested a special mechanism underlying the capability of flumatinib to overcome the drug-resistance conferred by activation loop mutations. These findings suggest that flumatinib could be a promising therapeutic agent against GISTs resistant to both imatinib and sunitinib because of secondary mutations in the activation loop.