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

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 () and Qiang Yu ()
Additional contact information
Yi Bao: National University of Singapore
Gokce Oguz: Genome Institute of Singapore, Agency for Science, Technology, and Research, Biopolis
Wee Chyan Lee: Genome Institute of Singapore, Agency for Science, Technology, and Research, Biopolis
Puay Leng Lee: Genome Institute of Singapore, Agency for Science, Technology, and Research, Biopolis
Kakaly Ghosh: Genome Institute of Singapore, Agency for Science, Technology, and Research, Biopolis
Jiayao Li: Jinan University
Panpan Wang: Jinan University
Peter E. Lobie: National University of Singapore
Sidse Ehmsen: University of Southern Denmark
Henrik J. Ditzel: University of Southern Denmark
Andrea Wong: National University Health System
Ern Yu Tan: Tan Tock Seng Hospital
Soo Chin Lee: National University of Singapore
Qiang Yu: Genome Institute of Singapore, Agency for Science, Technology, and Research, Biopolis

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19704-x

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