The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor
The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor
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DOI：
10.1158/1535-7163.mct-19-1148
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发表时间：
2020-07-01
影响因子：
5.7
通讯作者：
McDonnell, Donald P.
中科院分区：
文献类型：
--
作者：
Andreano, Kaitlyn J.;Baker, Jennifer G.;McDonnell, Donald P.
雌激素受体（ER/ESR 1）在大多数乳腺癌中表达，抑制ER信号传导的药物是乳腺癌药物治疗的基石。目前，芳香酶抑制剂是首选的一线内分泌干预措施，尽管它们在转移性疾病中的持久性受到ESRI配体结合结构域内允许受体的配体非依赖性激活的激活点突变的限制。有研究表明，当用作二线治疗时，最常见的ESRI突变可能会损害选择性雌激素受体下调剂和选择性雌激素受体调节剂（SERM）的临床活性。然而，目前尚不清楚这些可能在细胞中与ERWT共表达的突变如何以临床有意义的方式影响对ER配体的反应。为了解决这个问题，我们在转移性疾病相关模型中剖析了ESRI突变药理学的分子机制。这些研究表明，ESRI突变对配体的反应主要由ERWT在细胞中的相对共表达决定。具体而言，药理学失调仅在突变体相对于配体激活的ERWT过表达的细胞中明显;这一发现突出了等位性在确定ER突变体药理学中的作用。重要的是，我们证明了SERM的拮抗剂活性，lasofoxifene，不受突变状态的影响;这一发现导致其作为晚期ER阳性乳腺癌患者的治疗的临床评价，这些患者的肿瘤含有ESRI突变。
The estrogen receptor (ER/ESR1) is expressed in a majority of breast cancers and drugs that inhibit ER signaling are the cornerstone of breast cancer pharmacotherapy. Currently, aromatase inhibitors are the frontline endocrine interventions of choice although their durability in metastatic disease is limited by activating point mutations within the ligand-binding domain of ESRI that permit ligand-independent activation of the receptor. It has been suggested that the most commonly occurring ESRI mutations would likely compromise the clinical activity of selective estrogen receptor downregulators and selective estrogen receptor modulators (SERMs) when used as second-line therapies. It was unclear, however, how these mutations, which are likely coexpressed in cells with ERWT, may impact response to ER ligands in a clinically meaningful manner. To address this issue, we dissected the molecular mechanism(s) underlying ESRI-mutant pharmacology in models relevant to metastatic disease. These studies revealed that the response of ESRI mutations to ligands was dictated primarily by the relative coexpression of ERWT in cells. Specifically, dysregulated pharmacology was only evident in cells in which the mutants were overexpressed relative to ligand-activated ERWT; a finding that highlights the role of allelism in determining ER-mutant pharmacology. Importantly, we demonstrated that the antagonist activity of the SERM, lasofoxifene, was not impacted by mutant status; a finding that has led to its clinical evaluation as a treatment for patients with advanced ER-positive breast cancer whose tumors harbor ESRI mutations.