QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Radiation Biology Research Center, Institute for Radiological Research, Chang Gung Memorial Hospital/Chang Gung University, Taoyuan, Taiwan.
Int J Cancer. 2020 Jan 1;146(1):123-136. doi: 10.1002/ijc.32410. Epub 2019 May 31.
Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25-30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8 T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients.
三阴性乳腺癌（TNBCs）是一种非常侵袭性和致命性的乳腺癌，目前尚无有效的靶向治疗方法。新辅助化疗和放疗仍然是治疗的主要方法，但只有 25-30%的 TNBC 患者有反应。因此，迫切需要开发针对 TNBC 的新治疗策略。TNBC 细胞的细胞内氧化应激增加，谷胱甘肽（一种主要的抗氧化系统）受到抑制，但仍能抵抗更高的氧化应激。我们使用 TCGA 和 METABRIC 数据库筛选了一组抗氧化基因，发现与非 TNBC 患者相比，TNBC 患者的硫氧还蛋白途径基因表达显著上调，并且与不良生存结局相关。用 FDA 批准的硫氧还蛋白还原酶抑制剂 auranofin (AF) 治疗会导致特定的细胞死亡，并损害作为球体生长的 TNBC 细胞的生长。此外，AF 治疗在包括同源 4T1.2 模型、MDA-MB-231 异种移植和患者来源的肿瘤异种移植在内的多种 TNBC 模型中具有显著的体内抗肿瘤活性，抑制了硫氧还蛋白的氧化还原活性。我们首次表明，AF 通过 ERK1/2-MYC 依赖性方式增加了体内 CD8 T 细胞的肿瘤浸润，并上调了免疫检查点 PD-L1 的表达。此外，AF 与抗 PD-L1 抗体联合使用可协同损害 4T1.2 原发性肿瘤的生长。我们的数据提供了一种使用 AF 联合抗 PD-L1 抗体的新治疗策略，值得进一步为 TNBC 患者进行临床研究。
