Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases
Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases
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DOI：
10.1073/pnas.0504952102
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发表时间：
2005-08-02
影响因子：
11.1
通讯作者：
Lockhart, DJ
中科院分区：
文献类型：
--
作者：
Carter, TA;Wodicka, LM;Lockhart, DJ
为了充分发挥靶向蛋白激酶抑制剂治疗癌症的潜力，解决接受治疗的患者中出现的耐药性非常重要。已发现BCR-ABL、KIT和EGF受体（EGFR）的突变形式赋予对药物伊马替尼、吉非替尼和厄洛替尼的抗性。突变减弱或阻止药物结合，有趣的是，所有三种激酶中最常见的突变位点之一是激酶活性位点附近高度保守的“看门人”苏氨酸残基。我们已经确定了现有的临床化合物，结合和抑制ABL，KIT和EGFR的耐药突变体。我们发现Aurora激酶抑制剂VX-680和p38抑制剂BIRB-796抑制伊马替尼和BMS-354825耐药ABL（T315 I）激酶。KIT/FLT 3抑制剂SU-111248有效抑制伊马替尼耐药KIT（V559 D/T670 I）激酶，与SU-11248对伊马替尼耐药胃肠道肿瘤的临床疗效一致，与EGFR抑制剂EKB-569和CI-1033一致，但与GW-572016和ZD-6474不一致，强效抑制吉非替尼和厄洛替尼耐药EGFR（L 858 R/T790 M）激酶。EKB-569和CI-1033已经在临床试验中，我们的结果表明，它们应该被考虑用于吉非替尼/厄洛替尼耐药非小细胞肺癌的治疗。这些结果突出了针对新发现的耐药突变体筛选现有临床化合物的策略，以找到可能作为开发下一代药物的起点的化合物，或者可以直接用于治疗对第一代靶向治疗产生耐药性的患者。
To realize the full potential I 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-111248 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.