HER kinase inhibition in patients with HER2- and HER3-mutant cancers.
HER kinase inhibition in patients with HER2- and HER3-mutant cancers.
复制标题
DOI：
10.1038/nature25475
复制
发表时间：
2018-02-08
期刊：
影响因子：
64.8
通讯作者：
Solit DB
中科院分区：
文献类型：
--
作者：
Hyman DM;Piha-Paul SA;Won H;Rodon J;Saura C;Shapiro GI;Juric D;Quinn DI;Moreno V;Doger B;Mayer IA;Boni V;Calvo E;Loi S;Lockhart AC;Erinjeri JP;Scaltriti M;Ulaner GA;Patel J;Tang J;Beer H;Selcuklu SD;Hanrahan AJ;Bouvier N;Melcer M;Murali R;Schram AM;Smyth LM;Jhaveri K;Li BT;Drilon A;Harding JJ;Iyer G;Taylor BS;Berger MF;Cutler RE Jr;Xu F;Butturini A;Eli LD;Mann G;Farrell C;Lalani AS;Bryce RP;Arteaga CL;Meric-Bernstam F;Baselga J;Solit DB
ERBB 2（HER 2）和ERBB 3（HER 3）的体细胞突变在多种癌症中发现。临床前建模表明，一个子集导致组成型HER 2激活，但大多数仍然没有生物学特征。我们试图通过使用泛HER激酶抑制剂来那替尼（SUMMIT; Clinicaltrials.gov NCT 01953926）进行多组织学、基因组选择的“篮子”研究，前瞻性地确定已知致癌HER 2和HER 3突变以及未知生物学意义的变体的生物学和治疗意义。在HER 2突变型癌症中的疗效随肿瘤类型和突变等位基因的变化而变化，临床前模型无法预测，在乳腺癌、宫颈癌和胆管癌以及携带激酶结构域错义突变的肿瘤中观察到最大活性。这项研究表明，分子驱动的临床试验可用于进一步完善我们对特征性和新型基因组改变的生物学理解，具有潜在的广泛适用性，可用于推进基因组驱动的肿瘤学范式。
Somatic mutations of ERBB2 (HER2) and ERBB3 (HER3) are found in a wide range of cancers. Preclinical modelling suggests that a subset lead to constitutive HER2 activation, but most remain biologically uncharacterized. We sought to prospectively define the biologic and therapeutic significance of known oncogenic HER2 and HER3 mutations and variants of unknown biological significance by conducting a multi-histology, genomically selected, ‘basket’ study utilizing the pan-HER kinase inhibitor neratinib (SUMMIT; Clinicaltrials.gov 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 harbouring kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to further refine our biological understanding of both characterized and novel genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.
登录
查看更多内容
影响因子：
17.1
作者：
McGranahan N;Favero F;de Bruin EC;Birkbak NJ;Szallasi Z;Swanton C
通讯作者：
Swanton C
DOI：
10.1056/nejmoa1502309
发表时间：
2015-08-20
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hyman DM;Puzanov I;Subbiah V;Faris JE;Chau I;Blay JY;Wolf J;Raje NS;Diamond EL;Hollebecque A;Gervais R;Elez-Fernandez ME;Italiano A;Hofheinz RD;Hidalgo M;Chan E;Schuler M;Lasserre SF;Makrutzki M;Sirzen F;Veronese ML;Tabernero J;Baselga J
通讯作者：
Baselga J
影响因子：
45.3
作者：
Freedman, Rachel A.;Gelman, Rebecca S.;Lin, Nancy U.
通讯作者：
Lin, Nancy U.
影响因子：
5.8
作者：
Chmielecki, Juliann;Ross, Jeffrey S.;Stephens, Philip J.
通讯作者：
Stephens, Philip J.
影响因子：
45.3
作者：
Baselga, Jose;Cortes, Javier;Swain, Sandra M.
通讯作者：
Swain, Sandra M.