Journal Article

EZH2-mediated PP2A inactivation confers resistance to HER2-targeted breast cancer therapy

Li, Jiayao, Bao, Yi, Ghosh, Kakaly, Lobie, Peter E., Tan, Ern Yu, Oguz, Gokce, Ditzel, Henrik J., Wang, Panpan, Ehmsen, Sidse, Lee, Soo Chin, Lee, Puay Leng, Yu, Qiang, Lee, Wee Chyan, Wong, Andrea

2020

Overview

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. Resistance to anti-HER2 therapies in breast cancer remains a significant clinical challenge. Here, the authors demonstrate that EZH2 regulates response to HER2-targeting therapies in breast cancer, in part, by modulating the expression of PPP2R2B .

• Publisher: Nature Publishing Group UK,Nature Portfolio
• Subject: 13 / 13/1 / 13/106 / 13/51 / 13/89 / 38/90 / 45/15 / 631/337 / 631/67 / 631/67/1347 / 64/60 / 692/4028 / 82/80 / Animals / Antineoplastic Agents - administration & dosage / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Cell Line, Tumor / Drug Resistance, Neoplasm / Enhancer of Zeste Homolog 2 Protein - genetics / Enhancer of Zeste Homolog 2 Protein - metabolism / Female / Humanities and Social Sciences / Humans / Mice / Mice, Nude / multidisciplinary / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Protein Phosphatase 2 - genetics / Protein Phosphatase 2 - metabolism / Quinazolines - administration & dosage / Receptor, ErbB-2 - genetics / Receptor, ErbB-2 - metabolism / Ribosomal Protein S6 Kinases, 70-kDa - genetics / Ribosomal Protein S6 Kinases, 70-kDa - metabolism / Science / Science (multidisciplinary)