摘要
雌激素受体(ER)阳性乳腺癌内分泌治疗在一定程度上是有效的,但是内源性及获得性耐药现象一直是临床治疗的难题。ER是由ESR1基因编码的一种核蛋白,ESR1基因突变在ER阳性乳腺癌内分泌治疗耐药中具有重要作用,ESR1基因异常改变包括基因数量、基因重排以及错义点突变。ER配体结合域(LBD)突变的发现进一步加深了对内分泌耐药机制的理解。此外,研究表明,ER-LBD突变的激动构象和拮抗构象之间的动力学改变也可导致内分泌治疗耐药。目前,对内分泌治疗耐药的靶向治疗研究主要有提高氟维司群或他莫昔芬或其他选择性雌激素受体调节剂及选择性ER降解剂的剂量、靶向ER共激活因子(SRC-3抑制剂)或靶向ER信号通路下游的基因(CDK4/6抑制剂),新型药物的研究有望解决内分泌治疗的耐药问题。
Endocrine therapies are effective to estrogen receptor ct （ER） positive breast cancer. However, intrinsic-and ac- quired-endocrine resistance has always been the puzzle. ER is a nuclear protein, encoded by the ESR1 gene. ESR1 mutation plays an important role in endocrine resistance in ER positive breast cancer. ESRl-related genomic abnormalities include copy-number changes, genomic rearrangements and missense point mutation. The finding of ER ligand binding domain （LBD） mutations can deepen the un- derstanding of the endocrine resistance mechanisms. Furthermore, the dynamic changes between the agonist and antagonist conformation of the ER-LBD mutants can also result in endocrine resistance. Now, studies on the target therapy of endocrine resistance mainly focus on increasing the doses of fulvestrant or tamoxifen or more-potent selective estrin receptor modulators or estrogen receptor downregula- tors, new agents targeting ER co-activators, or targeting classical ER downstream genes （ CDK4/6 inhibitors）. The studies on new a- gents are expected to resolve the endocrine resistance problems.
出处
《临床肿瘤学杂志》
CAS
2016年第10期947-951,共5页
Chinese Clinical Oncology
