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EZH2-mediated PP2A inactivation confers resistance to HER2-targeted breast cancer therapy
Yi Bao1,2, Gokce Oguz2, Wee Chyan Lee2
1Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
Abstract:
HER2-targeted therapy has yielded a significant clinical benefit in patients with HER2+ breast cancer, yet disease relapse due to intrinsic or acquired resistance remains a significant challenge in the clinic. Here, we show that the protein phosphatase 2A (PP2A) regulatory subunit PPP2R2B is a crucial determinant of anti-HER2 response. PPP2R2B is downregulated in a substantial subset of HER2+ breast cancers, which correlates with poor clinical outcome and resistance to HER2-targeted therapies. EZH2-mediated histone modification accounts for the PPP2R2B downregulation, resulting in sustained phosphorylation of PP2A targets p70S6K and 4EBP1 which leads to resistance to inhibition by anti-HER2 treatments. Genetic depletion or inhibition of EZH2 by a clinically-available EZH2 inhibitor restores PPP2R2B expression, abolishes the residual phosphorylation of p70S6K and 4EBP1, and resensitizes HER2+ breast cancer cells to anti-HER2 treatments both in vitro and in vivo. Furthermore, the same epigenetic mechanism also contributes to the development of acquired resistance through clonal selection. These findings identify EZH2-dependent PPP2R2B suppression as an epigenetic control of anti-HER2 resistance, potentially providing an opportunity to mitigate anti-HER2 resistance with EZH2 inhibitors.
Insights
Downregulation of PPP2R2B protein, driven by EZH2, causes resistance to HER2-targeted therapies in breast cancer. Inhibiting EZH2 restores PPP2R2B, overcoming this resistance.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- HER2-targeted therapies offer clinical benefits for HER2+ breast cancer but face challenges from intrinsic and acquired resistance.
- Mechanisms underlying resistance to HER2-targeted treatments are not fully understood, hindering therapeutic efficacy.
Purpose of the Study:
- To investigate the role of Protein Phosphatase 2A (PP2A) regulatory subunit PPP2R2B in mediating resistance to HER2-targeted therapies.
- To elucidate the epigenetic mechanisms, specifically EZH2 involvement, responsible for PPP2R2B downregulation and subsequent therapeutic resistance.
Main Methods:
- Analysis of PPP2R2B expression in HER2+ breast cancer patient cohorts.
- Investigating the correlation between PPP2R2B levels, clinical outcomes, and response to HER2-targeted therapies.
- Utilizing genetic depletion and pharmacological inhibition of EZH2 (using a clinical EZH2 inhibitor) to assess its impact on PPP2R2B expression and downstream signaling.
- Evaluating the resensitization of HER2+ breast cancer cells to anti-HER2 treatments in vitro and in vivo.
Main Results:
- PPP2R2B is downregulated in a subset of HER2+ breast cancers, correlating with poor outcomes and resistance to HER2-targeted therapies.
- EZH2-mediated histone modification was identified as the mechanism for PPP2R2B downregulation, leading to sustained phosphorylation of p70S6K and 4EBP1.
- Genetic or pharmacological inhibition of EZH2 restored PPP2R2B expression, reduced p70S6K and 4EBP1 phosphorylation, and resensitized cancer cells to anti-HER2 treatments.
- The epigenetic mechanism involving EZH2 and PPP2R2B also contributes to acquired resistance through clonal selection.
Conclusions:
- EZH2-dependent suppression of PPP2R2B is a key epigenetic regulator of resistance to HER2-targeted therapies in breast cancer.
- Targeting EZH2 with available inhibitors presents a potential strategy to overcome both intrinsic and acquired resistance to anti-HER2 treatments.
- Restoring PPP2R2B expression via EZH2 inhibition offers a promising therapeutic avenue for improving patient outcomes in HER2+ breast cancer.
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