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Cell Rep ; 29(2): 249-257.e8, 2019 10 08.
Article in English | MEDLINE | ID: mdl-31597089

ABSTRACT

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 H3K27me3, 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 H3K27me3 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 H3K27me3 depletion in Trastuzumab-resistant disease.


Subject(s)
Histones/metabolism , Lysine/metabolism , Molecular Targeted Therapy , Receptor, ErbB-2/metabolism , Adult , Animals , Breast Neoplasms/drug therapy , Cell Line, Tumor , Drug Resistance, Neoplasm , Enhancer of Zeste Homolog 2 Protein/metabolism , Female , Humans , Interferon Type I/metabolism , Methylation , Mice , Models, Biological , Polycomb Repressive Complex 2/metabolism , Retroelements/genetics , Trastuzumab/therapeutic use , Up-Regulation
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