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Proc Natl Acad Sci U S A ; 119(31): e2201376119, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35878022

RESUMO

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.


Assuntos
Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Proteínas de Membrana , Proteínas Nucleares , Fosfoproteínas , Trastuzumab , Animais , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Quimiocina CXCL10 , Quimiocina CXCL11 , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade , Proteínas de Membrana/metabolismo , Camundongos , Recidiva Local de Neoplasia/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Receptor ErbB-2/genética , Transdução de Sinais , Trastuzumab/farmacologia
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