Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

作者：Todd A. Carter, Lisa M. Wodicka, Neil P. Shah, Anne Marie Velasco, Miles A. Fabian, Daniel K. Treiber, Zdravko V. Milanov, Corey E. Atteridge, William Biggs, Philip T. Edeen, M. Brawner Floyd, Julia M. Ford, Robert M. Grotzfeld, Sanna Herrgård, Darren E. Insko, Shamal A. Mehta, Hitesh Patel, William J. Pao, Charles L. Sawyers, HAROLD E. VARMUS, Patrick P. Zarrinkar, David J. Lockhart · 发表于：Proceedings of the National Academy of Sciences · 年份：2005 · DOI：10.1073/pnas.0504952102 · 被引用次数：556 · 研究领域：Chronic Myeloid Leukemia Treatments、Chronic Lymphocytic Leukemia Research、Multiple Myeloma Research and Treatments

To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved "gatekeeper" threonine residue near the kinase active site. We have identified existing clinical compounds that bind and inhibit drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib- and BMS-354825-resistant ABL(T315I) kinase. The KIT/FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D/T670I) kinase, consistent with the clinical efficacy of SU-11248 against imatinib-resistant gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not GW-572016 and ZD-6474, potently inhibit the gefitinib- and erlotinib-resistant EGFR(L858R/T790M) kinase. EKB-569 and CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of gefitinib/erlotinib-resistant non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find com...