EZH2-mediated PP2A inactivation confers resistance to HER2-targeted breast cancer therapy. (Nat Commun, Nov 2020)

/ 2020, Latest Happenings, Research / By

Yi Bao 1 2, Gokce Oguz 2, Wee Chyan Lee 2, Puay Leng Lee 2, Kakaly Ghosh 2, Jiayao Li 3, Panpan Wang 3, Peter E Lobie 1 4, Sidse Ehmsen 5, Henrik J Ditzel 5 6, Andrea Wong 7, Ern Yu Tan 8, Soo Chin Lee 9 10, Qiang Yu 11 12 13

Author Information

1Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
2Cancer Precision Medicine, Genome Institute of Singapore, Agency for Science, Technology, and Research, Biopolis, Singapore, 138672,
Singapore.
3Cancer Research Institute, Jinan University, Guangzhou, China.
4Tsinghua-Berkeley Shenzhen Institute, Guangdong Province and Shenzhen Bay Laboratory, Tsinghua University, Shenzhen, Guangdong Province, China.
5Department of Oncology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, 5230, Odense, Denmark.
6Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, 5230, Odense, Denmark.
7Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, 119047, Singapore.
8Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore.
9Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore. csilsc@nus.edu.sg.
10Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, 119047, Singapore. csilsc@nus.edu.sg.
11Cancer Precision Medicine, Genome Institute of Singapore, Agency for Science, Technology, and Research, Biopolis, Singapore, 138672, Singapore. yuq@gis.a-star.edu.sg.
12Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore. yuq@gis.a-star.edu.sg.
13Cancer and Stem Cell Biology, DUKE-NUS Graduate Medical School of Singapore, Singapore, 169857, Singapore. yuq@gis.a-star.edu.sg.

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.


PMID: 33208750 DOI: 10.1038/s41467-020-19704-x

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