Conclusions In summary, the results of this study demonstrate that different Kit mutations respond differently to motesanib or imatinib. This likely reflects differences in the molecules’ mode of action. The data also show that motesanib is active against Kit mutations associated with resistance, suggesting that it may have clinical utility in the treatment of

patients with primary and secondary imatinib-resistant GIST. Acknowledgements The authors wish to acknowledge Douglas Whittington and Joseph Kim (Amgen Inc., Cambridge, MA) for generating the model of motesanib bound to Kit. Additionally, the authors would like to thank Ali Hassan, PhD (Complete Healthcare Communications, Inc.), whose work was funded by Amgen Inc., and Beate Quednau, PhD (Amgen Inc.), for their assistance in the preparation of this manuscript. References 1. Heinrich selleck kinase inhibitor MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS,

Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003, 21:4342–4349.PubMedCrossRef 2. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y: Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Erastin mw Science 1998, 279:577–580.PubMedCrossRef 3. Corless CL, Compound C mouse McGreevey L, Haley A, Town A, Heinrich MC: KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol 2002, 160:1567–1572.PubMedCrossRef 4. Corless CL, Fletcher JA, Heinrich MC: Biology of gastrointestinal stromal tumors. J Clin Oncol 2004, 22:3813–3825.PubMedCrossRef

5. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA: PDGFRA activating mutations FAD in gastrointestinal stromal tumors. Science 2003, 299:708–710.PubMedCrossRef 6. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002, 347:472–480.PubMedCrossRef 7. Frost MJ, Ferrao PT, Hughes TP, Ashman LK: Juxtamembrane mutant V560GKit is more sensitive to Imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant.