Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity
Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity
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DOI：
10.1016/j.ccell.2019.09.001
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发表时间：
2019-10-14
期刊：
影响因子：
50.3
通讯作者：
Heymach, John, V
中科院分区：
文献类型：
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作者：
Robichaux, Jacqulyne P.;Elamin, Yasir Y.;Heymach, John, V
我们描述了癌症中ERBB2(HER2)突变的情况和药物敏感性。在11个数据集(n=211,726)中，ERBB2突变热点在25种肿瘤类型中不同。常见的HER2突变体在体外对11种EGFR/HER2酪氨酸激酶抑制剂(TKI)具有不同的敏感性，分子动力学模拟表明，药物结合口袋体积减少的突变体与较大TKI的亲和力降低有关。总体而言，poziotinib是HER2突变选择性TKI测试中最有效的。在ERBB2外显子20突变的非小细胞肺癌的II期临床测试中，在前12名可评估的患者中，确认的客观有效率为42%。在临床前模型中，Poziotinib上调了HER2细胞表面的表达，增强了T-DM1的活性，导致联合治疗后肿瘤完全消退。
We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.