从合成致死策略谈三阴性乳腺癌的靶向治疗

Studies on targeted therapy for triple-negative breast cancer based on synthetic lethal strategy

三阴性乳腺癌(triple negative breast cancer,TNBC)是指雌激素受体(estrogen receptor,ER)、孕激素受体(progesteronereceptor,PR)及人表皮生长因子受体-2(human epidermal growth factor receptor-2,HER-2)均为阴性表达的乳腺癌。该亚型好发于年轻女性,侵袭性强,组织学分级高,易发生内脏转移,生存期短,预后较差。针对TNBC的治疗手段有限,其对内分泌治疗及以HER-2为靶点的靶向治疗无效。合成致死策略是指两个基因中,若仅其中的一个基因发生了变异,细胞会仍然存活,若两个基因同时发生了变异,则将引起细胞死亡。在所涉及的两个基因中,若一个突变基因是癌基因,另外的一个基因就有可能成为潜在的"靶基因",那么针对其靶点的抑制剂可以杀死伴有癌变的恶性肿瘤细胞,但不会影响正常细胞的存活,即选择性杀死肿瘤细胞。基于合成致死策略寻找TNBC的新治疗靶点为研发抗TNBC新药提供了新的策略,与乳腺癌易感基因BRCA1协同修复DNA损伤的分子生物学机制显示PARP-1是TNBC的新靶点之一,PARP-1抑制剂有可能成为抗TNBC的新靶向治疗药物。

Triple-negative breast cancer （TNBC） is a subtype of breast cancer defined by the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 （Her-2）. TNBC is characterized by its onset among females at a very young age, high invasiveness and histological grades, and easy metastasis to the internal organs. This type of breast cancer is prone to visceral metastases and rapid progression, thereby resulting in short survival and unfavorable prognosis. Therapeutic tools against TNBC are limited because endocrine- and Her-2-targeted therapies are both ineffective. Synthetic lethal strategy means that two genetic mutations cause cell death. However, cells survive if only one mutation gene exists in the case. In these two mutation genes, if one is the oncogene, the other can become the potential ＂target gene.＂ This targeted inhibitor can then selectively kill malignant tumor cells through gene mutation, i.e., it can selectively kill the tumor without harming normal cells. This strategy of lethal synthesis for studies on new drugs against TNBC provides innovative ideas. Meanwhile, the breast cancer susceptibility gene BRCA-1 can synergistically repair DNA damage with poly（ADP-ribose） polymerase 1 （PARP-1）. PARP-1 is reportedly one of the new targets, and PARP-1 inhibitors can become a new drug for anti-TNBC targeted therapy.