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Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases.
Carter TA, Wodicka LM, Shah NP, Velasco AM, Fabian MA, Treiber DK, Milanov ZV, Atteridge CE, Biggs WH, Edeen PT, Floyd M, Ford JM, Grotzfeld RM, Herrgard S, Insko DE, Mehta SA, Patel HK, Pao W, Sawyers CL, Varmus H, Zarrinkar PP, Lockhart DJ
(2005) Proc Natl Acad Sci U S A 102: 11011-6
MeSH Terms: Aminoquinolines, Aniline Compounds, Cell Line, Drug Resistance, Neoplasm, ErbB Receptors, Humans, Indoles, Kinetics, Morpholines, Mutation, Naphthalenes, Neoplasms, Oncogene Proteins v-abl, Organic Chemicals, Piperazines, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-kit, Pyrazoles, Pyrroles, Sunitinib
Show Abstract · Added March 24, 2014
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 compounds that may serve as starting points for the development of next-generation drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy.
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20 MeSH Terms
Tyrosine kinase inhibitors: why does the current process of clinical development not apply to them?
Arteaga CL, Baselga J
(2004) Cancer Cell 5: 525-31
MeSH Terms: Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Benzamides, Cell Line, Tumor, Clinical Trials as Topic, Enzyme Inhibitors, ErbB Receptors, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mutation, Oncogene Proteins v-abl, Piperazines, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-kit, Pyrimidines, Receptor, ErbB-2, Trastuzumab
Show Abstract · Added March 5, 2014
The robust clinical activity of imatinib and trastuzumab for treatment of chronic myeloid leukemia, gastrointestinal stromal tumors, and breast cancer has demonstrated that blocking pathogenic tyrosine kinases can alter the natural history of human tumors. On the other hand, EGF receptor inhibitors have shown overall modest activity. The contrast in the development of these agents implies that both molecular target dependence and patient selection are essential for the successful outcome of this process. We will contrast lessons derived from the development of inhibitors of Abl, c-Kit, HER2/neu (erbB2), and EGFR, highlight successes and limitations in the field, and propose new approaches for clinical development of tyrosine kinase inhibitor therapy.
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18 MeSH Terms