Therapeutic approaches to ER mutant breast cancer

靶向乳腺癌雌激素受体（ER）的药物在治疗乳腺癌方面非常成功， 控制许多患者的疾病，然而经常遇到获得性耐药性。我们 已经在ER的配体结合结构域（LBD）中鉴定出高百分比的复发性突变， 有这种获得性抵抗的患者。我们发现两种最常见的突变促进了 尽管不存在配体，但激动剂构象引起对芳香酶抑制剂（AI）的抗性， 与不良的临床结果相关，并且可能被某些ER拮抗剂靶向。但我们 最近发现临床ESR1突变谱的存在。我们的数据显示 是不同突变体改变ER功能的机制的多样性， 不同突变对ER构象和活性的影响。这个项目的总体假设是 不同的ER LBD突变具有促进某种程度的雌激素非依赖性的能力， 受体活性，但在驱动肿瘤表型和促进药物治疗方面具有独特的效力。 阻力在这项提案中，我们将建立不同的ESR1突变的机制， 促进ER活性，表征由不同突变驱动的基因表达程序， 了解不同突变对ER抑制敏感性的影响，确定可能的途径， ER突变型疾病中ER拮抗剂的耐药性，并开发合理的组合以持久治疗 ER突变型癌症。为了实现这些目标，我们将产生ER突变体进入的细胞系模型， 已被敲入和患者来源的类器官和异种移植模型。我们将评估现有的ER 拮抗剂，并开发新的抑制剂，以确定有效抑制各种ER突变体的化合物。 最后，我们将使用体外筛选和肿瘤活检来表征可能的耐药机制 新的ER拮抗剂和提名的药理学策略，以克服这些。

Drugs targeting the estrogen receptor (ER) in breast cancer have been extremely successful in controlling the disease for many patients, however acquired resistance is frequently encountered. We have identified recurrent mutations in the ligand binding domain (LBD) of ER among a high percentage of patients with such acquired resistance. We have found that the two most frequent mutations promote an agonist conformation despite the absence of ligand, cause resistance to aromatase inhibitors (AI), associate with poor clinical outcomes, and may be targeted by certain ER antagonists. However, we have more recently found that a spectrum of clinical ESR1 mutations exists. Our data reveal that there is diversity in the mechanisms whereby different mutants alter ER function as well as diversity in the impact of different mutations on ER conformation and activity. The overall hypothesis of this project is that different ER LBD mutations share an ability to promote some level of estrogen-independent receptor activity but have distinctive potencies in driving tumor phenotypes and promoting drug resistance. In this proposal, we will establish the mechanisms whereby different ESR1 mutations promote ER activity, characterize the gene expression programs driven by different mutations, understand the implications of different mutations for sensitivity to ER inhibition, identify likely routes of resistance to ER antagonists in ER mutant disease, and develop rational combinations to durably treat ER mutant cancer. To accomplish these goals, we will generate cell line models into which ER mutants have been knocked-in and patient derived organoid and xenograft models. We will evaluate existing ER antagonists and develop novel inhibitors to identify compounds that potently inhibit various ER mutants. Finally, we will use in vitro screens and tumor biopsies to characterize likely mechanisms of resistance to newer ER antagonists and nominate pharmacologic strategies to overcome these.