Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
Case Comprehensive Cancer Center, Case Western University, Cleveland, OH 44145, USA.
Cell Rep. 2019 Oct 8;29(2):249-257.e8. doi: 10.1016/j.celrep.2019.08.105.
Monoclonal antibodies (mAbs) targeting the oncogenic receptor tyrosine kinase ERBB2/HER2, such as Trastuzumab, are the standard of care therapy for breast cancers driven by ERBB2 overexpression and activation. However, a substantial proportion of patients exhibit de novo resistance. Here, by comparing matched Trastuzumab-naive and post-treatment patient samples from a neoadjuvant trial, we link resistance with elevation of H3K27me, a repressive histone modification catalyzed by polycomb repressor complex 2 (PRC2). In ErbB2+ breast cancer models, PRC2 silences endogenous retroviruses (ERVs) to suppress anti-tumor type-I interferon (IFN) responses. In patients, elevated H3K27me in tumor cells following Trastuzumab treatment correlates with suppression of interferon-driven viral defense gene expression signatures and poor response. Using an immunocompetent model, we provide evidence that EZH2 inhibitors promote interferon-driven immune responses that enhance the efficacy of anti-ErbB2 mAbs, suggesting the potential clinical benefit of epigenomic reprogramming by H3K27me depletion in Trastuzumab-resistant disease.
针对致癌受体酪氨酸激酶 ERBB2/HER2 的单克隆抗体（mAbs），如曲妥珠单抗，是 ERBB2 过表达和激活驱动的乳腺癌的标准治疗方法。然而，相当一部分患者表现出原发耐药。在这里，我们通过比较一项新辅助试验中配对的曲妥珠单抗初治和治疗后患者样本，将耐药性与 H3K27me 的升高联系起来，H3K27me 是由多梳抑制复合物 2（PRC2）催化的一种抑制性组蛋白修饰。在 ErbB2+乳腺癌模型中，PRC2 沉默内源性逆转录病毒（ERVs）以抑制抗肿瘤 I 型干扰素（IFN）反应。在患者中，曲妥珠单抗治疗后肿瘤细胞中 H3K27me 的升高与干扰素驱动的病毒防御基因表达特征的抑制和不良反应相关。使用免疫功能正常的模型，我们提供了证据表明，EZH2 抑制剂促进干扰素驱动的免疫反应，增强了抗 ErbB2 mAbs 的疗效，这表明在曲妥珠单抗耐药疾病中通过 H3K27me 耗竭进行表观基因组重编程的潜在临床益处。
