Reduction of Global H3K27me3 Enhances HER2/ErbB2 Targeted Therapy
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. Muller
Affiliations
Alison Hirukawa
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada
Salendra Singh
Case Comprehensive Cancer Center, Case Western University, Cleveland, OH 44145, USA
Jarey Wang
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Jonathan P. Rennhack
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
Matthew Swiatnicki
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
Virginie Sanguin-Gendreau
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada
Dongmei Zuo
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada
Kamilia Daldoul
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada
Cynthia Lavoie
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada
Morag Park
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
Eran R. Andrechek
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
Thomas F. Westbrook
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
Lyndsay N. Harris
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
Vinay Varadan
Case Comprehensive Cancer Center, Case Western University, Cleveland, OH 44145, USA
Harvey W. Smith
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Corresponding author
William J. Muller
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada; Corresponding author
Summary: 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. : Hirukawa et al. link Trastuzumab resistance in ErbB2+ breast cancers with activity of the methyltransferase EZH2, a key epigenetic regulator. By silencing retrotransposons, EZH2 suppresses type-I interferon signaling to limit immune surveillance. Retrotransposon de-repression following EZH2 inhibition triggers interferon responses and sensitizes immunocompetent in vivo models to ErbB2 antibody therapy. Keywords: ErbB2/HER2, breast cancer, Polycomb Repressor Complex 2, PRC2, epigenetics, Trastuzumab resistance, endogenous retroviruses, immune surveillance, type I interferon signaling, transcriptional silencing
