逆转乳腺癌患者靶向治疗耐药的新靶点
22年来，曲妥珠单抗等HER2靶向治疗药物已为HER2阳性乳腺癌患者带来了显著的临床获益。不过，仍有将近一半患者对HER2靶向治疗原发或继发耐药，造成乳腺癌复发，这一直是困扰临床医师的巨大难题。
2020年11月18日，英国《自然》旗下《自然通讯》在线发表新加坡国立大学杨潞龄医学院、新加坡科技研究局基因组研究所、新加坡国立大学癌症中心、新加坡陈笃生医院、杜克新加坡国立大学医学研究生院、中国暨南大学肿瘤研究所、清华大学伯克利深圳学院、南丹麦大学欧登塞医院、南丹麦大学分子医学研究所的研究报告，探讨了乳腺癌HER2靶向治疗耐药机制。
该研究表明，蛋白质磷酸酶PP2A调节亚基PPP2R2B是HER2靶向治疗效果的关键决定因素。大多数HER2阳性乳腺癌患者的PPP2R2B表达水平显著较低，与临床结局不佳和HER2靶向治疗耐药密切相关。
组蛋白甲基转移酶EZH2对组蛋白的甲基化修饰作用可引起PPP2R2B表达水平显著较低，导致PP2A靶蛋白P70S6K和4EBP1持续磷酸化，从而抑制HER2靶向治疗。
通过基因技术耗尽EZH2，或者利用临床现有EZH2抑制剂，可恢复PPP2R2B表达，阻止P70S6K和4EBP1继续磷酸化，并使HER2阳性乳腺癌细胞对体内和体外HER2靶向治疗重新敏感。
此外，相同的表观遗传机制也有助乳腺癌通过克隆选择产生继发耐药。
因此，该研究结果表明，EZH2通过表观遗传控制可抑制PPP2R2B，引起PP2A失活，造成乳腺癌对HER2靶向治疗耐药，EZH2抑制剂有助于逆转乳腺癌对HER2靶向治疗耐药。
Nat Commun. 2020 Nov 18;11(1):5878.
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, Qiang Yu.
Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Genome Institute of Singapore, Agency for Science, Technology, and Research, Biopolis, Singapore, Singapore; National University Cancer Institute, National University Health System, Singapore, Singapore; Tan Tock Seng Hospital, Singapore, Singapore; DUKE-NUS Graduate Medical School of Singapore, Singapore, Singapore; Cancer Research Institute, Jinan University, Guangzhou, China; Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen, Guangdong, China; Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
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.
DOI: 10.1038/s41467-020-19704-x