曲妥珠单抗
癌症研究
EZH2型
组蛋白脱乙酰基酶
免疫系统
组蛋白脱乙酰酶抑制剂
生物
刺
乳腺癌
表观遗传学
免疫学
癌症
医学
组蛋白
内科学
基因
生物化学
工程类
航空航天工程
作者
Li-Teng Ong,Wee Chyan Lee,Shijun Ma,Gokce Oguz,Zhitong Niu,Bao Yi,Mubaraka Yusuf,Puay Leng Lee,Jian Yuan Goh,Panpan Wang,Kylie Su Mei Yong,Qingfeng Chen,Wenyu Wang,Adaikalavan Ramasamy,Dave S. B. Hoon,Henrik J. Ditzel,Ern Yu Tan,Soo Chin Lee,Qiang Yu
标识
DOI:10.1073/pnas.2201376119
摘要
Relapse to anti-HER2 monoclonal antibody (mAb) therapies, such as trastuzumab in HER2+ breast cancer (BC), is associated with residual disease progression due to resistance to therapy. Here, we identify interferon-γ inducible protein 16 (IFI16)-dependent STING signaling as a significant determinant of trastuzumab responses in HER2+ BC. We show that down-regulation of immune-regulated genes (IRG) is specifically associated with poor survival of HER2+, but not other BC subtypes. Among IRG, IFI16 is identified as a direct target of EZH2, the underexpression of which leads to deficient STING activation and downstream CXCL10/11 expression in response to trastuzumab treatment. Dual inhibition of EZH2 and histone deacetylase (HDAC) significantly activates IFI16-dependent immune responses to trastuzumab. Notably, a combination of a novel histone methylation inhibitor with an HDAC inhibitor induces complete tumor eradication and long-term T cell memory in a HER2+ BC mouse model. Our findings demonstrate an epigenetic regulatory mechanism suppressing the expression of the IFI16-CXCL10/11 signaling pathway that provides a survival advantage to HER2+ BC to confer resistance to trastuzumab treatment.
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