2. Academic Validation
  3. Reduction of Global H3K27me3 Enhances HER2/ErbB2 Targeted Therapy

Reduction of Global H3K27me3 Enhances HER2/ErbB2 Targeted Therapy

  • Cell Rep. 2019 Oct 8;29(2):249-257.e8. doi: 10.1016/j.celrep.2019.08.105.
Alison Hirukawa 1,  Salendra Singh 2,  Jarey Wang 3,  Jonathan P Rennhack 4,  Matthew Swiatnicki 4,  Virginie Sanguin-Gendreau 1,  Dongmei Zuo 1,  Kamilia Daldoul 1,  Cynthia Lavoie 1,  Morag Park 5,  Eran R Andrechek 4,  Thomas F Westbrook 6,  Lyndsay N Harris 7,  Vinay Varadan 2,  Harvey W Smith 8,  William J Muller 9
Affiliations

Affiliations

  • 1 Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
  • 2 Case Comprehensive Cancer Center, Case Western University, Cleveland, OH 44145, USA.
  • 3 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 4 Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
  • 5 Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Departments of Medicine and Oncology, McGill University, Montréal, QC H3A 1A3, Canada.
  • 6 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Interdepartmental Program in Molecular and Biomedical Sciences, Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, and Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 7 Case Comprehensive Cancer Center, Case Western University, Cleveland, OH 44145, USA; Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Rockville, MD 20892, USA.
  • 8 Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada. Electronic address: [email protected].
  • 9 Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada. Electronic address: [email protected].
PMID: 31597089 DOI: 10.1016/j.celrep.2019.08.105
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.

Keywords

ErbB2/HER2; PRC2; Polycomb Repressor Complex 2; Trastuzumab resistance; breast cancer; endogenous retroviruses; epigenetics; immune surveillance; transcriptional silencing; type I interferon signaling.

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