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波齐替尼可有效治疗ERBB2基因突变肿瘤
作者:小柯机器人 发布时间:2019/10/6 18:27:54

美国德州大学MD安德森癌症中心John V. Heymach研究小组取得一项新进展。他们通过分析泛肿瘤中的ERBB2基因突变,发现波齐替尼(Poziotinib)是一种有活性的抑制剂并可增强T-DM1药物活性。2019年10月3日,《癌细胞》在线发表了这项成果。

研究人员鉴定了ERBB2(HER2)基因突变在癌症中的情况和药物敏感性。在11个数据集中(n=211726),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(TKI)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较大TKI的亲和力降低相关。总体而言,波齐替尼是测试过的最有效的HER2突变体选择性TKI。在ERBB2第20个外显子突变非小细胞肺癌的II期临床试验中,在前12名可评估的患者中,确认的客观缓解率为42%。在临床前模型中,波齐替尼上调HER2细胞表面表达并增强T-DM1的活性,从而通过联合治疗使肿瘤完全消退。

附:英文原文

Title: Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity

Author: Jacqulyne P. Robichaux, Yasir Y. Elamin, R.S.K. Vijayan, Monique B. Nilsson, Lemei Hu, Junqin He, Fahao Zhang, Marlese Pisegna, Alissa Poteete, Huiying Sun, Shuai Li, Ting Chen, Han Han, Marcelo Vailati Negrao, Jordi Rodon Ahnert, Lixia Diao, Jing Wang, Xiuning Le, Funda Meric-Bernstam, Mark Routbort, Brent Roeck, Zane Yang, Victoria M. Raymond, Richard B. Lanman, Garrett M. Frampton, Vincent A. Miller, Alexa B. Schrock, Lee A. Albacker, Kwok-kin Wong, Jason B. Cross, John V. Heymach

Issue&Volume: 3 October 2019

Abstract: 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.

DOI: 10.1016/j.ccell.2019.09.001

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30384-8

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:23.916
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx