Department of Discovery Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
Cancer Discov. 2013 Feb;3(2):168-81. doi: 10.1158/2159-8290.CD-12-0357. Epub 2012 Dec 10.
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 EGF receptor (EGFR) T790M "gatekeeper" substitution, prompting efforts to develop covalent EGFR inhibitors, which can effectively suppress EGFR T790M in preclinical 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 that spare wild-type EGFR. These findings show the use 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.
EGFR-mutant lung cancer patients who respond to currently used EGFR kinase inhibitors invariably develop drug resistance, which is associated with the EGFR T790M resistance mutation in about half these cases. We unexpectedly identified a class of reversible potent inhibitors of EGFR T790M that do not inhibit wild-type EGFR, revealing a promising therapeutic strategy to overcome T790M-associated drug-resistant lung cancers.
大约一半的表皮生长因子受体（EGFR）突变型非小细胞肺癌（NSCLC）患者在接受小分子 EGFR 激酶抑制剂治疗后会产生与 EGFR 受体（EGFR）T790M“守门员”取代相关的耐药性，这促使人们努力开发共价 EGFR 抑制剂，该抑制剂在临床前模型中能有效抑制 EGFR T790M。然而，这些抑制剂尚未证明在临床上有效，其在皮肤中的毒性，反映了对野生型 EGFR 的活性，可能会限制有效抑制体内 EGFR T790M 所需的剂量。在对大型癌细胞系面板进行各种激酶抑制剂敏感性分析时，我们鉴定了吲哚咔唑化合物，包括一种临床耐受良好的 FLT3 抑制剂，它们是 EGFR T790M 的有效且可逆抑制剂，可保留野生型 EGFR。这些发现表明，使用广泛的癌症细胞激酶抑制剂功效分析来确定意外的新应用，并确定吲哚咔唑化合物在 NSCLC 中 T790M 介导的耐药性情况下可能是有效的 EGFR 抑制剂。
对目前使用的 EGFR 激酶抑制剂有反应的 EGFR 突变型肺癌患者不可避免地会产生耐药性，其中约有一半的耐药性与 EGFR T790M 耐药突变有关。我们意外地发现了一类对 EGFR T790M 具有有效且可逆抑制作用的抑制剂，而不会抑制野生型 EGFR，这为克服与 T790M 相关的耐药性肺癌提供了一种很有前途的治疗策略。
