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

• DOI: 10.1038/s41467-020-19704-x
• Publication Date: 2020-11-18T11:05:54Z
• Authors: Yi Bao; Gokce Oguz; Wee Chyan Lee; Puay Leng Lee; Kakaly Ghosh; Jiayao Li; Panpan Wang; Peter E. Lobie; Sidse Ehmsen; Henrik J. Ditzel; Andrea Wong; Ern Yu Tan; Soo Chin Lee; Qiang Yu
• Keywords: 0303 health sciences; Receptor, ErbB-2; Science; Q; 610; Mice, Nude; Ribosomal Protein S6 Kinases, 70-kDa; Antineoplastic Agents; Breast Neoplasms; Nerve Tissue Proteins; Article; 3. Good health; Mice; 03 medical and health sciences; Drug Resistance, Neoplasm; Cell Line, Tumor; Quinazolines; Animals; Humans; Enhancer of Zeste Homolog 2 Protein; Female; Protein Phosphatase 2

AbstractHER2-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.