Noncovalent wild-type-sparing inhibitors of EGFR T790M.
Noncovalent wild-type-sparing inhibitors of EGFR T790M.
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DOI：
10.1158/2159-8290.cd-12-0357
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发表时间：
2013-02
期刊：
影响因子：
28.2
通讯作者：
Settleman J
中科院分区：
文献类型：
--
作者：
Lee HJ;Schaefer G;Heffron TP;Shao L;Ye X;Sideris S;Malek S;Chan E;Merchant M;La H;Ubhayakar S;Yauch RL;Pirazzoli V;Politi K;Settleman J
接受小分子EGFR激酶抑制剂治疗的EGFR突变型非小细胞肺癌（NSCLC）患者中，约有一半发生与EGFR T790 M“看门人”取代相关的耐药性，这促使人们努力开发共价EGFR抑制剂，其可在临床前模型中有效抑制EGFR T790 M。然而，这些抑制剂尚未证明临床上有效，并且它们在皮肤中的毒性（反映了对野生型EGFR的活性）可能限制有效抑制体内EGFR T790M所需的剂量。在分析对大型癌细胞系面板中的各种激酶抑制剂的敏感性时，我们鉴定了吲哚并咔唑化合物，包括临床上耐受良好的FLT3抑制剂，作为EGFR T790M的有效和可逆抑制剂，其使野生型EGFR不受影响。这些发现证明了激酶抑制剂功效的广泛癌细胞谱分析用于鉴定意外的新应用的实用性，并且它们鉴定了吲哚并咔唑化合物作为NSCLC中T790M介导的耐药性背景下的潜在有效的EGFR抑制剂。
Approximately half of EGFR mutant non-small cell lung cancer (NSCLC) patients treated with small molecule EGFR kinase inhibitors develop drug resistance associated with the EGFR T790M “gatekeeper” substitution, prompting efforts to develop covalent EGFR inhibitors, which can effectively suppress EGFR T790M in pre-clinical models. However, these inhibitors have yet to prove clinically efficacious, and their toxicity in skin, reflecting activity against wild-type EGFR, may limit dosing required to effectively suppress EGFR T790M in vivo. While profiling sensitivity to various kinase inhibitors across a large cancer cell line panel, we identified indolocarbazole compounds, including a clinically well-tolerated FLT3 inhibitor, as potent and reversible inhibitors of EGFR T790M, which spare wild-type EGFR. These findings demonstrate the utility of broad cancer cell profiling of kinase inhibitor efficacy to identify unanticipated novel applications, and they identify indolocarbazole compounds as potentially effective EGFR inhibitors in the context of T790M-mediated drug resistance in NSCLC.