Biological mechanisms and clinical implications of endocrine resistance in breast cancer
Biological mechanisms and clinical implications of endocrine resistance in breast cancer
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DOI：
10.1016/s0960-9776(11)70293-4
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发表时间：
2011-10-01
期刊：
影响因子：
3.9
通讯作者：
Trivedi, Meghana V.
中科院分区：
文献类型：
--
作者：
Giuliano, Mario;Schiff, Rachel;Trivedi, Meghana V.
内分泌治疗是雌激素受体阳性(ER+)乳腺癌妇女的第一种也是最有效的靶向治疗。在过去的40年里，一些激素类药物被成功地引入临床实践，既可以作为晚期疾病的姑息治疗，也可以作为预防肿瘤复发的辅助治疗。然而，很大一部分患者会出现内在和获得性耐药，限制了内分泌治疗的疗效。内分泌抵抗的分子机制已被提出。ER表达缺失、ER协同调节因子活性改变、细胞凋亡和细胞周期信号转导失控、高活性受体酪氨酸激酶(RTK)和应激/细胞激酶通路共同调控内分泌治疗耐药的发生和维持。临床前和临床证据表明，ER表达水平和信号转导具有可塑性。因此，内质网既可以直接驱动基因转录和肿瘤进展，也可以与交替的RTK和细胞激酶信号通路串扰，导致其自身表达水平和转录程序的调节。因此，一种基于针对ER和RTK信号通路的药物的组合的治疗方法代表了一种有希望的有待测试的策略。在许多RTK中，EGFR、HER2和PI3K已被发现是联合治疗策略的可行靶点，至少在临床前环境中是这样。然而，测试联合策略的临床试验的早期结果并不一致，这表明需要更好的方法来同时抑制多条逃逸途径，并选择可能从这些策略中受益最大的患者。(C)2011爱思唯尔有限公司。保留所有权利。
Endocrine therapy represents the first and most efficacious targeted treatment for women with estrogen receptor-positive (ER+) breast cancer. In the last four decades several hormonal agents have been successfully introduced in clinical practice as both palliative therapy for advanced disease and adjuvant treatment for prevention of tumor relapse. Nevertheless, the intrinsic and acquired resistance occurs in a significant proportion of patients, limiting the efficacy of endocrine treatments. Several molecular mechanisms have been proposed to be responsible for endocrine resistance. Loss of ER expression, altered activity of ER coregulators, deregulation of apoptosis and cell cycle signaling, and hyperactive receptor tyrosine kinase (RTK) and stress/cell kinase pathways can collectively orchestrate the development and sustenance of pharmacologic resistance to endocrine therapy. Preclinical and clinical evidence documents the plasticity in ER expression levels and signaling. As such, ER can either drive gene transcription and tumor progression directly or crosstalk with alternate RTK and cellular kinase signaling pathways, resulting in modulation of its own expression levels and transcriptional program. For this reason a therapeutic approach based on the combination of agents targeting both ER and RTK signaling represents a promising strategy to be tested. Among many RTKs, EGFR, HER2, and PI3K have been found to be viable targets for the combination therapy strategy, at least in the preclinical setting. However, early results from clinical trials testing combination strategies have been discordant, suggesting the need for better approaches to simultaneously inhibit multiple escape pathways and to select the patients who may benefit the most from these strategies. (c) 2011 Elsevier Ltd. All rights reserved.