Health Research Institute, Faculty of ESTeM, University of Canberra, Canberra, ACT, Australia.
Department of Medical Oncology, The Canberra Hospital, Canberra, ACT, Australia.
Cancer Sci. 2018 Nov;109(11):3383-3392. doi: 10.1111/cas.13799. Epub 2018 Oct 20.
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor survival outcomes. Currently, there are no targeted therapies available for TNBCs despite remarkable progress in targeted and immune-directed therapies for other solid organ malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective anticancer drugs that produce good initial clinical responses, especially in homologous recombination DNA repair-deficient cancers. However, resistance is the rule rather than the exception, and recurrent tumors tend to have an aggressive phenotype associated with poor survival. Many efforts have been made to overcome PARPi resistance, mostly by targeting genes and effector proteins participating in homologous recombination that are overexpressed during PARPi therapy. Due to many known and unknown compensatory pathways, genes, and effector proteins, overlap and shared resistance are common. Overexpression of programmed cell death-ligand 1 (PD-L1) and cancer stem cell (CSC) sparing are novel PARPi resistance hypotheses. Although adding programmed cell death-1 (PD-1)/PD-L1 inhibitors to PARPi might improve immunogenic cell death and be crucial for durable responses, they are less likely to target the CSC population that drives recurrent tumor growth. Lysine-specific histone demethylase-1A and histone deacetylase inhibitors have shown promising activity against CSCs. Combining epigenetic drugs such as lysine-specific histone demethylase-1A inhibitors or histone deacetylase inhibitors with PARPi/anti-PD-1/PD-L1 is a novel, potentially synergistic strategy for priming tumors and overcoming resistance. Furthermore, such an approach could pave the way for the identification of new upstream epigenetic and genetic signatures.
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，生存预后较差。尽管在其他实体器官恶性肿瘤的靶向和免疫治疗方面取得了显著进展，但目前仍没有针对 TNBC 的靶向治疗方法。聚 ADP-核糖聚合酶抑制剂（PARPi）是有效的抗癌药物，能产生良好的初始临床反应，尤其在同源重组 DNA 修复缺陷型癌症中。然而，耐药是普遍现象，而复发性肿瘤往往具有侵袭性表型，与生存预后不良相关。为克服 PARPi 耐药，人们进行了许多努力，主要是通过靶向在 PARPi 治疗过程中过表达的参与同源重组的基因和效应蛋白。由于存在许多已知和未知的补偿途径、基因和效应蛋白，重叠和共同耐药很常见。程序性细胞死亡配体 1（PD-L1）和癌症干细胞（CSC）的过表达是新的 PARPi 耐药假说。尽管添加程序性细胞死亡-1（PD-1）/PD-L1 抑制剂到 PARPi 中可能改善免疫原性细胞死亡并对持久应答至关重要，但它们不太可能针对驱动复发性肿瘤生长的 CSC 群体。赖氨酸特异性组蛋白去甲基化酶 1A 和组蛋白去乙酰化酶抑制剂对 CSCs 显示出有希望的活性。将表观遗传药物（如赖氨酸特异性组蛋白去甲基化酶 1A 抑制剂或组蛋白去乙酰化酶抑制剂）与 PARPi/抗 PD-1/PD-L1 联合使用是一种新的、潜在的协同策略，可以启动肿瘤并克服耐药性。此外，这种方法可能为鉴定新的上游表观遗传和遗传特征铺平道路。
