Reduction of Global H3K27me Enhances HER2/ErbB2 Targeted Therapy.

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ID: 59221
2019
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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 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.
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hirukawa2019reductioncell Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Hirukawa, Alison;Singh, Salendra;Wang, Jarey;Rennhack, Jonathan P;Swiatnicki, Matthew;Sanguin-Gendreau, Virginie;Zuo, Dongmei;Daldoul, Kamilia;Lavoie, Cynthia;Park, Morag;Andrechek, Eran R;Westbrook, Thomas F;Harris, Lyndsay N;Varadan, Vinay;Smith, Harvey W;Muller, William J;
Journal Cell reports
Year 2019
DOI
S2211-1247(19)31167-2
URL
Keywords
Breast cancer epigenetics transcriptional silencing erbb2/her2 prc2 polycomb repressor complex 2 trastuzumab resistance endogenous retroviruses immune surveillance type i interferon signaling

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