波齊替尼可有效治療ERBB2基因突變腫瘤



本期文章:《癌細胞》:Online/在線發表

美國德州大學MD安德森癌癥中心John V. Heymach研究小組取得一項新進展。他們通過分析泛腫瘤中的ERBB2基因突變,發現波齊替尼(Poziotinib)是一種有活性的抑制劑并可增強T-DM1藥物活性。2019年10月3日,《癌細胞》在線發表了這項成果。

研究人員鑒定了ERBB2(HER2)基因突變在癌癥中的情況和藥物敏感性。在11個數據集中(n=211726),ERBB2突變熱點在25種腫瘤類型中有所不同。常見的HER2突變體在體外對11種EGFR/HER2酪氨酸激酶抑制劑(TKI)產生不同的敏感性,并且分子動力學模擬顯示,藥物結合袋體積減小的突變體與較大TKI的親和力降低相關??傮w而言,波齊替尼是測試過的最有效的HER2突變體選擇性TKI。在ERBB2第20個外顯子突變非小細胞肺癌的II期臨床試驗中,在前12名可評估的患者中,確認的客觀緩解率為42%。在臨床前模型中,波齊替尼上調HER2細胞表面表達并增強T-DM1的活性,從而通過聯合治療使腫瘤完全消退。

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:《癌細胞》,創刊于2002年。隸屬于細胞出版社,最新IF:23.916
官方網址:https://www.cell.com/cancer-cell/home
投稿鏈接:https://www.editorialmanager.com/cancer-cell/default.aspx




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