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Reduction of Global H3K27me3 Enhances HER2/ErbB2 Targeted Therapy
Alison Hirukawa1, Salendra Singh2, Jarey Wang3
1Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
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.
Insights
Resistance to Trastuzumab in HER2+ breast cancer is linked to elevated H3K27me3, which silences anti-tumor immunity. Inhibiting EZH2 may restore immune responses and improve treatment efficacy in resistant disease.
Area of Science:
- Oncology
- Epigenetics
- Immunology
Background:
- Monoclonal antibodies (mAbs) targeting ERBB2/HER2, like Trastuzumab, are standard care for ERBB2+ breast cancer.
- A significant number of patients develop resistance to Trastuzumab therapy.
- Understanding resistance mechanisms is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the epigenetic mechanisms underlying Trastuzumab resistance in ERBB2+ breast cancer.
- To explore the role of histone modification H3K27me3 and polycomb repressor complex 2 (PRC2) in treatment resistance.
- To evaluate the therapeutic potential of targeting PRC2 for overcoming resistance.
Main Methods:
- Comparative analysis of Trastuzumab-naive and post-treatment patient samples from a neoadjuvant trial.
- Assessment of H3K27me3 levels and PRC2 activity in tumor cells.
- Evaluation of endogenous retroviral (ERV) silencing and type-I interferon (IFN) responses.
- Utilizing immunocompetent breast cancer models to test EZH2 inhibitors in combination with anti-ErbB2 mAbs.
Main Results:
- Trastuzumab resistance in patients was associated with elevated H3K27me3 levels.
- Elevated H3K27me3 correlated with suppressed interferon-driven viral defense gene expression.
- PRC2 was found to silence ERVs, thereby suppressing anti-tumor type-I IFN responses in ErbB2+ breast cancer models.
- EZH2 inhibitors enhanced anti-tumor immune responses and improved the efficacy of anti-ErbB2 mAbs in preclinical models.
Conclusions:
- Elevated H3K27me3 is a biomarker and potential driver of Trastuzumab resistance in ERBB2+ breast cancer.
- Epigenomic reprogramming by depleting H3K27me3 may overcome resistance by restoring anti-tumor immunity.
- Targeting EZH2 offers a promising strategy to enhance the effectiveness of anti-HER2 therapies in resistant breast cancer.
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