EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor
EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor
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DOI：
10.1158/0008-5472.can-15-2581
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发表时间：
2016-03-15
期刊：
影响因子：
11.2
通讯作者：
Kasibhatla, Shailaja
中科院分区：
文献类型：
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作者：
Jia, Yong;Juarez, Jose;Kasibhatla, Shailaja
携带致癌EGFR突变的非小细胞肺癌患者最初对EGFR靶向治疗有反应，但后来由于剂量限制毒性和获得性耐药而引起极小的反应。EGF816是一种新型的、不可逆的突变选择性EGFR抑制剂，它特异性地针对从头开始和在获得耐药性时激活EGFR的突变，同时保留野生型(WT)EGFR。EGF816在体外有效地抑制了最常见的EGFR突变L858R、Ex19del和T790M，这些突变在几个患者来源的异种移植模型中在体内转化为强大的肿瘤退化。值得注意的是，EGF816在外显子20插入突变模型中也显示了抗肿瘤活性。在高于有效剂量的水平上，EGF816治疗导致对WT EGFR的最小抑制，且耐受性良好。在单剂量研究中，EGF816提供了对EGFR磷酸化的持续抑制，与其不可逆结合的能力一致。此外，EGF816和cMET抑制剂INC280的联合治疗在异种移植模型中产生了持久的抗肿瘤效果，该模型最初通过cMET激活对第一代EGFR抑制剂产生抗药性。因此，我们首次报道了EGF816的临床前特征，并为目前在携带EGFR突变的患者(包括T790M)的I/II期临床试验中对其进行评估奠定了基础。(C)2016年AACR。
Non-small cell lung cancer patients carrying oncogenic EGFR mutations initially respond to EGFR-targeted therapy, but later elicit minimal response due to dose-limiting toxicities and acquired resistance. EGF816 is a novel, irreversible mutant-selective EGFR inhibitor that specifically targets EGFR-activating mutations arising de novo and upon resistance acquisition, while sparing wild-type (WT) EGFR. EGF816 potently inhibited the most common EGFR mutations L858R, Ex19del, and T790M in vitro, which translated into strong tumor regressions in vivo in several patient-derived xenograft models. Notably, EGF816 also demonstrated antitumor activity in an exon 20 insertion mutant model. At levels above efficacious doses, EGF816 treatment led to minimal inhibition of WT EGFR and was well tolerated. In single-dose studies, EGF816 provided sustained inhibition of EGFR phosphorylation, consistent with its ability for irreversible binding. Furthermore, combined treatment with EGF816 and INC280, a cMET inhibitor, resulted in durable antitumor efficacy in a xenograft model that initially developed resistance to first-generation EGFR inhibitors via cMET activation. Thus, we report the first preclinical characterization of EGF816 and provide the groundwork for its current evaluation in phase I/II clinical trials in patients harboring EGFR mutations, including T790M. (C) 2016 AACR.