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Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity.
Cancer Cell ( IF 48.8 ) Pub Date : 2019-10-03 , DOI: 10.1016/j.ccell.2019.09.001 Jacqulyne P Robichaux 1 , Yasir Y Elamin 1 , R S K Vijayan 2 , Monique B Nilsson 1 , Lemei Hu 1 , Junqin He 1 , Fahao Zhang 1 , Marlese Pisegna 1 , Alissa Poteete 1 , Huiying Sun 1 , Shuai Li 3 , Ting Chen 3 , Han Han 3 , Marcelo Vailati Negrao 1 , Jordi Rodon Ahnert 4 , Lixia Diao 5 , Jing Wang 6 , Xiuning Le 1 , Funda Meric-Bernstam 4 , Mark Routbort 6 , Brent Roeck 7 , Zane Yang 7 , Victoria M Raymond 8 , Richard B Lanman 8 , Garrett M Frampton 9 , Vincent A Miller 9 , Alexa B Schrock 9 , Lee A Albacker 9 , Kwok-Kin Wong 3 , Jason B Cross 2 , John V Heymach 1
Cancer Cell ( IF 48.8 ) Pub Date : 2019-10-03 , DOI: 10.1016/j.ccell.2019.09.001 Jacqulyne P Robichaux 1 , Yasir Y Elamin 1 , R S K Vijayan 2 , Monique B Nilsson 1 , Lemei Hu 1 , Junqin He 1 , Fahao Zhang 1 , Marlese Pisegna 1 , Alissa Poteete 1 , Huiying Sun 1 , Shuai Li 3 , Ting Chen 3 , Han Han 3 , Marcelo Vailati Negrao 1 , Jordi Rodon Ahnert 4 , Lixia Diao 5 , Jing Wang 6 , Xiuning Le 1 , Funda Meric-Bernstam 4 , Mark Routbort 6 , Brent Roeck 7 , Zane Yang 7 , Victoria M Raymond 8 , Richard B Lanman 8 , Garrett M Frampton 9 , Vincent A Miller 9 , Alexa B Schrock 9 , Lee A Albacker 9 , Kwok-Kin Wong 3 , Jason B Cross 2 , John V Heymach 1
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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.
中文翻译：
泛癌态势和ERBB2突变分析确定Poziotinib是T-DM1活性的临床活性抑制剂和增强剂。
我们表征了ERBB2（HER2）突变在癌症中的态势和药物敏感性。在11个数据集中（n = 211,726），ERBB2突变热点在25种肿瘤类型中有所不同。常见的HER2突变体在体外对11种EGFR / HER2酪氨酸激酶抑制剂（TKIs）产生不同的敏感性，并且分子动力学模拟显示，药物结合袋体积减小的突变体与对较大TKI的亲和力降低相关。总体而言，泊齐替尼是测试过的最有效的HER2突变体选择性TKI。在ERBB2外显子20突变非小细胞肺癌的II期临床试验中，在前12名可评估患者中，确认的客观缓解率为42％。在临床前模型中，poziotinib上调HER2细胞表面表达并增强T-DM1的活性，
更新日期：2019-11-09
中文翻译：
泛癌态势和ERBB2突变分析确定Poziotinib是T-DM1活性的临床活性抑制剂和增强剂。
我们表征了ERBB2（HER2）突变在癌症中的态势和药物敏感性。在11个数据集中（n = 211,726），ERBB2突变热点在25种肿瘤类型中有所不同。常见的HER2突变体在体外对11种EGFR / HER2酪氨酸激酶抑制剂（TKIs）产生不同的敏感性，并且分子动力学模拟显示，药物结合袋体积减小的突变体与对较大TKI的亲和力降低相关。总体而言，泊齐替尼是测试过的最有效的HER2突变体选择性TKI。在ERBB2外显子20突变非小细胞肺癌的II期临床试验中，在前12名可评估患者中，确认的客观缓解率为42％。在临床前模型中，poziotinib上调HER2细胞表面表达并增强T-DM1的活性，
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