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¹ Cancer Research UK Viral Oncology Group and ² Biological and Medicinal Chemistry Group, Wolfson Institute for Biomedical Research, University College London; ³ Department of Histopathology, Royal Free and University College London Hospitals; ⁴ University College London Hospitals, London, United Kingdom and ⁵ Discovery Ltd., Cambridge, United Kingdom

Requests for reprints: David Selwood, Biological and Medicinal Chemistry Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom. E-mail: d.selwood{at}ucl.ac.uk

Several activating mutations in the cKIT receptor tyrosine kinase are associated with the development and progression of gastrointestinal stromal tumors (GIST). Treatment of GIST with the tyrosine kinase inhibitor imatinib (Gleevec, STI571; Novartis, Basel, Switzerland) increases patient survival. However, many patients develop resistance to imatinib following initial responses. We sequenced cKIT exons from two patients with GIST after the development of imatinib resistance, revealing a point mutation in kinase domain I (exon 13), Val⁶⁵⁴Ala, which has been associated previously with relapse and resistance. Molecular modeling of cKIT-imatinib complexes shows that this residue is located in the drug-binding site and that the Val⁶⁵⁴Ala mutation disrupts drug binding by removing hydrophobic contacts with the central diaminophenyl ring of imatinib. Loss of these contacts results in a destabilizing effect on two key hydrogen bonds between imatinib and Asp³¹⁰ and Thr⁶⁷⁰ of cKIT. Calculations based on published crystallography data show an estimated destabilization energy of 2.25 kcal/mol in the Val⁶⁵⁴Ala cKIT compared with wild type. When present on the same cKIT allele as an oncogenic mutation, the Val⁶⁵⁴Ala mutation abolishes imatinib-mediated inhibition of cKIT phosphoactivation in vitro. These results highlight some of the structural and functional consequences of the Val⁶⁵⁴Ala mutation in relapsing imatinib-resistant GIST and emphasize the importance of tumor genetics in drug development and patient-specific cancer treatment regimens. [Mol Cancer Ther 2005;4(12):2005–15]

⁶ http://swift.cmbi.kun.nl/WIWWWI/.

Received 3/11/05; revised 9/28/05; accepted 10/19/05.