Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.

中文翻译：

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非小细胞肺癌中EGFR和HER2外显子20选择性激酶抑制剂的机制和临床活性。

尽管大多数表皮生长因子受体（EGFR）突变非小细胞肺癌（NSCLC）的激活突变对可用的EGFR酪氨酸激酶抑制剂（TKIs）敏感，但EGFR和HER2外显子20发生改变的子集具有内在抵抗力，缺乏有效的治疗方法。我们使用了计算机模拟，体外和体内测试，以模拟由外显子20突变诱导的结构改变，并确定有效的抑制剂。3D建模表明，变化限制了药物结合袋的大小，从而限制了大型刚性抑制剂的结合。我们发现poziotinib由于其体积小和柔韧性好，可以规避这些空间变化，并且是最常见的EGFR和HER2外显子20突变体的有效抑制剂。在体外以及在患者衍生的EGFR或HER2外显子20突变型NSCLC的异种移植模型以及基因工程化的NSCLC小鼠模型中，Poziotinib均比批准的EGFR TKIs具有更高的活性。在一项2期试验中，前11名患有EGFR外显子20突变的NSCLC患者接受了poziotinib的确诊客观缓解率为64％。这些数据确定了poziotinib是EGFR和HER2外显子20突变的有力，临床活性抑制剂，并阐明了TKI的分子特征，这些分子特征可能会规避由这些突变引起的空间变化。