Reduction of Global H3K27me3 Enhances HER2/ErbB2 Targeted Therapy
Publication date: 8 October 2019Source: Cell Reports, Volume 29, Issue 2Author(s): Alison Hirukawa, Salendra Singh, Jarey Wang, Jonathan P. Rennhack, Matthew Swiatnicki, Virginie Sanguin-Gendreau, Dongmei Zuo, Kamilia Daldoul, Cynthia Lavoie, Morag Park, Eran R. Andrechek, Thomas F. Westbrook, Lyndsay N. Harris, Vinay Varadan, Harvey W. Smith, William J. MullerSummaryMonoclonal 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...
Source: Cell Reports - Category: Cytology Source Type: research
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