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

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

doi:10.1038/s41467-020-19704-x

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.

Highlights

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
In addition to distant metastasis-free survival (DMFS), PPP2R2B downregulation, among the seven candiates, is associated with poor relapse-free survival (RFS) (Supplementary Fig. 1a), as well as poor overall survival (OS) in HER2+ breast cancer patients (Supplementary Fig. 1b). In both public database and our in-house patient specimens, PPP2R2B downregulation occurred in about 50% of HER2+ breast cancers compared to normal tissues (Supplementary Fig. 1c, d). These findings suggest that PPP2R2B downregulation occurs in a substantial proportion of HER2+ breast cancers, and is associated with a higher risk of disease progression
We discovered an epigenetic mechanism leading to resistance to anti-HER2 therapy that is mediated by EZH2-mediated phosphatase 2A (PP2A) inhibition

Summary

Introduction

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. 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. Despite this, nearly half of such patients still suffer disease relapse due to intrinsic or acquired resistance to the treatments[3,4], demonstrating the failure of stratifying breast cancer patients who will benefit from HER2-targeted therapy based solely on HER2 status. Activated PI3K/AKT/mTOR signaling has been implicated in anti-HER2 resistance, a more effective therapeutic strategy targeting the pathway is needed to overcome the resistance. The role of the PP2A family in breast cancer oncogenesis and in modulating the response to anti-HER2 therapies has yet to be characterized

Methods

Results

Conclusion