Structural-Transcriptional Relationships that Improve Y537S Estrogen Receptor Antagonism

摘要 本研究旨在研究药物诱导的Y537S雌激素受体α(ER-α)的结构变化如何影响抗-HBs。 荷尔蒙抵抗的乳腺癌细胞中的肿瘤活动。乳腺癌是第二大致癌原因。 美国的死亡案例。对激素治疗的获得性抵抗是导致死亡的主要因素。在……里面 大约40%的进展性ER+患者，通过抗雌激素治疗延长了选择性压力， 提高到具有激活的体细胞esr1(ERα基因)突变的肿瘤。这些突变抵抗抑制。 通过临床批准的激素疗法和参与新的转录程序来促进转移 潜力。Y537S错义突变是最常见的突变之一，可以使最大程度的无激素 转录活性与抗雌激素抵抗。下一代选择性雌激素受体降解剂 (SERD)已经在临床上用于解决这种耐药机制。然而，他们显示 Y537S ESR1在乳腺癌中的不同活性，并具有限制其长期生存的常见副作用 使用。我们最近研究了17个选择性雌激素受体调节剂(SERM)和SERD是如何结合的 对乳腺癌细胞Y537S ERα活性的影响。我们确定了结构上不同的SERM和SERD 在这一背景下，活动有所改善。虽然结构截然不同，但我们的x射线共晶结构表明 大多数有效的分子结合了相同的S537-E380氢键来加强治疗拮抗剂 构象。因此，我们假设新的配体依赖的结构相互作用将会改善。 Y537S ESR1环境中的治疗拮抗活性。在这项研究中，我们将利用我们的超过 100种不同的SERM和SERD揭示结构-转录关系 Y537S ESR1乳腺癌细胞的抗癌活性。我们将从研究我们的图书馆如何绑定和影响开始 Y537S ERα结构与抗癌活性(目标1)。这一方法将揭示配体结合模式和 结构上的相互作用，使之具有效力。接下来，我们将研究最有效的分子如何影响Y537S ERα基因组活性包括蛋白质-蛋白质相互作用、基因组结合和转录编程 (目标2)。这种方法将显示SERM和SERD的有效性是否源于对Y537S的更改 ERα基因组活性。最后，我们将揭示抗肿瘤和组织特异性活性的最有效 激素抵抗ER+乳腺癌体内的SERM和SERD(目标3)。这种方法将揭示出 我们的体外观察与患者相关肿瘤模型中抗癌活性的改善相一致。总的来说， 这些研究将提供详细的结构-转录关系，以改善靶向治疗 Y537S ERα在激素抵抗型乳腺癌中的作用

Summary This proposal studies how drug-induced structural changes to Y537S estrogen receptor alpha (ERα) impact anti- tumoral activities in hormone-resistant breast cancer cells. Breast cancer is the second leading cause of cancer death in the United States. Acquired resistance to hormone therapies is a leading contributor to mortality. In approximately 40% of progressive ER+ patients, prolonged selective pressure by antiestrogenic therapies gives raise to tumors bearing activating somatic ESR1 (the gene for ERα) mutations. These mutations resist inhibition by clinically approved hormone therapies and engage new transcriptional programs that boost metastatic potential. Y537S missense mutation is among the most common and enables the greatest hormone-free transcriptional activities and resistance to antiestrogen. Next generation selective estrogen receptor degraders (SERDs) have been clinically deployed to address this mechanism of drug resistance. However, they show variable activities in Y537S ESR1 breast cancers and possess common side-effects that will limit their long-term use. We recently studied how a panel of 17 selective estrogen receptor modulators (SERMs) and SERDs bind to and affect Y537S ERα activities in breast cancer cells. We identified structurally distinct SERMs and SERDs with improved activities in this setting. While structurally distinct, our x-ray co-crystal structures showed that the most effective molecules engaged the same S537-E380 hydrogen bond to reinforce the therapeutic antagonist conformation. Therefore, we hypothesize that novel ligand-dependent structural interactions will improve therapeutic antagonistic activities in the Y537S ESR1 setting. In this study, we will leverage our library of over 100 diverse SERMs and SERDs to reveal the structural-transcriptional relationships that underlie improved anti- cancer activities Y537S ESR1 breast cancer cells. We will start by studying how our library binds to and affects Y537S ERα structure and anti-cancer activities (Aim 1). This approach will reveal the ligand binding modes and structural interactions that enable potency. Next, we will study how the most effective molecules impact Y537S ERα genomic activities including protein-protein interactions, genome binding, and transcriptional programing (Aim 2). This approach will show whether the efficacies of SERMs and SERDs arise from alterations to Y537S ERα genomic activities. Finally, we will reveal the anti-tumor and tissue-specific activities of the most effective SERMs and SERDs in hormone-resistant ER+ breast cancer in vivo (Aim 3). This approach will reveal whether our in vitro observations correspond to improved anti-cancer activities in patient-relevant tumor models. Overall, these studies will provide detailed structural-transcriptional relationships to improve therapeutic targeting of Y537S ERα in hormone-resistant breast cancer.