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HER kinase inhibition in patients with HER2- and HER3-mutant cancers
Nature ( IF 50.5 ) Pub Date : 2018-01-31 , DOI: 10.1038/nature25475
David M Hyman 1 , Sarina A Piha-Paul 2 , Helen Won 1 , Jordi Rodon 3 , Cristina Saura 3 , Geoffrey I Shapiro 4 , Dejan Juric 5 , David I Quinn 6 , Victor Moreno 7 , Bernard Doger 7 , Ingrid A Mayer 8 , Valentina Boni 9 , Emiliano Calvo 9 , Sherene Loi 10 , Albert C Lockhart 11 , Joseph P Erinjeri 1 , Maurizio Scaltriti 1 , Gary A Ulaner 1 , Juber Patel 1 , Jiabin Tang 1 , Hannah Beer 1 , S Duygu Selcuklu 1 , Aphrothiti J Hanrahan 1 , Nancy Bouvier 1 , Myra Melcer 1 , Rajmohan Murali 1 , Alison M Schram 1 , Lillian M Smyth 1 , Komal Jhaveri 1 , Bob T Li 1 , Alexander Drilon 1 , James J Harding 1 , Gopa Iyer 1 , Barry S Taylor 1 , Michael F Berger 1 , Richard E Cutler 12 , Feng Xu 12 , Anna Butturini 12 , Lisa D Eli 12 , Grace Mann 12 , Cynthia Farrell 12 , Alshad S Lalani 12 , Richard P Bryce 12 , Carlos L Arteaga 8 , Funda Meric-Bernstam 2 , José Baselga 1 , David B Solit 1
Nature ( IF 50.5 ) Pub Date : 2018-01-31 , DOI: 10.1038/nature25475
David M Hyman 1 , Sarina A Piha-Paul 2 , Helen Won 1 , Jordi Rodon 3 , Cristina Saura 3 , Geoffrey I Shapiro 4 , Dejan Juric 5 , David I Quinn 6 , Victor Moreno 7 , Bernard Doger 7 , Ingrid A Mayer 8 , Valentina Boni 9 , Emiliano Calvo 9 , Sherene Loi 10 , Albert C Lockhart 11 , Joseph P Erinjeri 1 , Maurizio Scaltriti 1 , Gary A Ulaner 1 , Juber Patel 1 , Jiabin Tang 1 , Hannah Beer 1 , S Duygu Selcuklu 1 , Aphrothiti J Hanrahan 1 , Nancy Bouvier 1 , Myra Melcer 1 , Rajmohan Murali 1 , Alison M Schram 1 , Lillian M Smyth 1 , Komal Jhaveri 1 , Bob T Li 1 , Alexander Drilon 1 , James J Harding 1 , Gopa Iyer 1 , Barry S Taylor 1 , Michael F Berger 1 , Richard E Cutler 12 , Feng Xu 12 , Anna Butturini 12 , Lisa D Eli 12 , Grace Mann 12 , Cynthia Farrell 12 , Alshad S Lalani 12 , Richard P Bryce 12 , Carlos L Arteaga 8 , Funda Meric-Bernstam 2 , José Baselga 1 , David B Solit 1
Affiliation
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Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, ‘basket’ trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.
中文翻译：
HER2 和 HER3 突变癌症患者的 HER 激酶抑制
ERBB2 和 ERBB3（分别编码 HER2 和 HER3）的体细胞突变存在于多种癌症中。临床前建模表明，这些突变的一个子集导致组成型 HER2 激活，但大多数在生物学上仍未表征。在这里，我们通过使用泛 HER 激酶抑制剂奈拉替尼 （SUMMIT;clinicaltrials.gov 标识符 NCT01953926） 进行多组织学、基因组选择的“篮子”试验，定义了已知致癌 HER2 和 HER3 突变以及生物学重要性未知的变体的生物学和治疗重要性。HER2 突变癌症的疗效因肿瘤类型和突变等位基因而异，其程度无法通过临床前模型预测，在乳腺癌、宫颈癌和胆道癌以及包含激酶结构域错义突变的肿瘤中可见最活跃。本研究展示了如何使用分子驱动的临床试验来完善我们对特征和新基因组改变的生物学理解，并可能广泛适用于推进基因组驱动肿瘤学的范式。
更新日期：2018-01-31
中文翻译：
HER2 和 HER3 突变癌症患者的 HER 激酶抑制
ERBB2 和 ERBB3（分别编码 HER2 和 HER3）的体细胞突变存在于多种癌症中。临床前建模表明，这些突变的一个子集导致组成型 HER2 激活，但大多数在生物学上仍未表征。在这里，我们通过使用泛 HER 激酶抑制剂奈拉替尼 （SUMMIT;clinicaltrials.gov 标识符 NCT01953926） 进行多组织学、基因组选择的“篮子”试验，定义了已知致癌 HER2 和 HER3 突变以及生物学重要性未知的变体的生物学和治疗重要性。HER2 突变癌症的疗效因肿瘤类型和突变等位基因而异，其程度无法通过临床前模型预测，在乳腺癌、宫颈癌和胆道癌以及包含激酶结构域错义突变的肿瘤中可见最活跃。本研究展示了如何使用分子驱动的临床试验来完善我们对特征和新基因组改变的生物学理解，并可能广泛适用于推进基因组驱动肿瘤学的范式。
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