小柯机器人

近日，美国德州大学西南医学中心Ariella B. Hanker等研究人员发现，HER2和HER3中共同发生的功能获得性突变调节HER2/HER3激活、肿瘤发生和HER2抑制剂敏感性。这一研究成果于2021年6月24日在线发表在国际学术期刊《癌细胞》上。

研究人员表示，HER2（ERBB2）中的激活突变会推动一部分乳腺癌和其他癌症的生长，并且往往与HER3（ERBB3）错义突变同时发生。HER2酪氨酸激酶抑制剂来那替尼已显示出对HER2突变肿瘤的临床活性。

为了表征HER3突变在HER2突变肿瘤中的作用，研究人员将计算结构建模与生化和细胞生物学分析相结合。计算模型预测，频繁的HER3^E928G激酶结构域突变增强了HER2/HER3的亲和力并降低了HER2与其抑制剂来那替尼的结合。突变型HER2/HER3的共表达增强了HER2/HER3共免疫沉淀和HER2/HER3和PI3K/AKT的配体非依赖性激活，导致生长、侵袭性和对HER2靶向治疗的耐药性增强，这可通过联合应用逆转用PI3Kα抑制剂治疗。

这些结果为共同发生的HER2/HER3突变的进化选择以及最近的临床观察提供了一个机制原理，即HER3突变与HER2突变癌症中对来那替尼的不良反应有关。

附：英文原文

Title: Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity

Author: Ariella B. Hanker, Benjamin P. Brown, Jens Meiler, Arnaldo Marín, Harikrishna S. Jayanthan, Dan Ye, Chang-Ching Lin, Hiroaki Akamatsu, Kyung-Min Lee, Sumanta Chatterjee, Dhivya R. Sudhan, Alberto Servetto, Monica Red Brewer, James P. Koch, Jonathan H. Sheehan, Jie He, Alshad S. Lalani, Carlos L. Arteaga

Issue&Volume: 2021-06-24

Abstract: Activating mutations in HER2 (ERBB2) drive the growth of a subset of breast and other cancers and tend to co-occur withHER3 (ERBB3) missense mutations. The HER2 tyrosine kinase inhibitor neratinib has shown clinicalactivity against HER2-mutant tumors. To characterize the role of HER3 mutations in HER2-mutant tumors, we integrate computational structural modeling with biochemical andcell biological analyses. Computational modeling predicts that the frequent HER3E928G kinase domain mutation enhances the affinity of HER2/HER3 and reduces binding ofHER2 to its inhibitor neratinib. Co-expression of mutant HER2/HER3 enhances HER2/HER3co-immunoprecipitation and ligand-independent activation of HER2/HER3 and PI3K/AKT,resulting in enhanced growth, invasiveness, and resistance to HER2-targeted therapies,which can be reversed by combined treatment with PI3Kα inhibitors. Our results providea mechanistic rationale for the evolutionary selection of co-occurring HER2/HER3 mutations and the recent clinical observations that HER3 mutations are associated with a poor response to neratinib in HER2-mutant cancers.

DOI: 10.1016/j.ccell.2021.06.001

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00284-1

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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