Defining mechanisms of resistance to hormonal therapy in breast cancer

摘要 激素治疗仍然是系统治疗70%表现出 雌激素受体(ER)，但反应各不相同，内在和获得性耐药是主要的临床挑战。 最近发现雌激素受体(ER)基因(ESR1)的配体结合域发生突变， 以调解大约35%ER阳性(ER+)乳腺癌患者的激素治疗抵抗。在……里面 其余三分之二的病例，激素治疗抵抗的分子基础很大程度上是未知的。在……里面 基于1756例复发或转移乳腺癌患者的靶向测序的初步数据 疾病，我们确定了MAP激酶信号的不同效应因子(ERBB2突变， ESR1野生型乳腺癌中的EGFR扩增、NF1突变等) 抗雌激素治疗的研究进展。这一提议是基于这样一种假设，即最近在 无细胞dna(Cfdna)的测序方法学和分析可以前瞻性地识别分子改变。 使乳腺癌患者对激素治疗产生抵抗力，并共同针对这种变化 与内质网并用可防止或延缓耐药克隆的出现。三个具体目标是 建议。在目标1中，配对的肿瘤样本和乳腺癌患者在治疗前和治疗期间收集的cfDNA 治疗和在疾病进展时的激素治疗将被用来定义景观和 在选择性治疗压力下出现的分子变化的时间。我们的初步数据显示 ERBB2突变是激素治疗固有和获得性耐药的一种机制。我们有 还发现HER激酶抑制剂neratinib可以引起有限的深刻治疗反应。 通过诱导内质网活性，从而产生耐药性。因此，在目标2中，我们将使用 配对的预处理和疾病进展的肿瘤活检，cfDNA定期收集在 单独使用neratinib或使用ER降解剂fulvestrant，以及设计的等基因模型和 患者来源的异种移植，以识别和验证对这些治疗药物的耐药机制。 最后，我们的基因组分析在以下收集的肿瘤中发现了约10%的RAS/ERK通路变化 荷尔蒙治疗的疾病进展。在目标3中，我们将探索这一发现的功能意义 并寻求开发治疗策略，以克服这种分子上的激素治疗抵抗 定义的人口。该项目的长期目标是开发ER+乳腺的治疗策略 实时、非侵入性的肿瘤分子监测指导下的肿瘤演变。拟议的工作还将 建立有价值的HER2突变和NF1突变ER+乳腺癌的临床前模型，可用于 未来的研究将评估对这些分子定义的人群有前景的新治疗方法。

ABSTRACT Hormonal therapy remains a mainstay of systemic treatment for the 70% of breast cancers that express the estrogen receptor (ER), but responses vary and intrinsic and acquired resistance are major clinical challenges. Recently, ligand-binding domain mutations in the estrogen receptor (ER) gene (ESR1) were found to occur and to mediate hormonal therapy resistance in approximately 35% of ER-positive (ER+) breast cancer patients. In the remaining two-thirds of cases, the molecular basis of hormonal therapy resistance is largely unknown. In preliminary data, based on targeted sequencing of 1756 breast cancer patients with recurrent or metastatic disease, we identified enrichment for alterations in diverse effectors of MAP kinase signaling (ERBB2 mutation, EGFR amplification, NF1 mutation, and others) in ESR1-wildtype breast cancers collected after disease progression on anti-estrogen therapy. This proposal is based on the hypothesis that recent advances in sequencing methodology and analysis of cell-free DNA (cfDNA) can prospectively identify molecular alterations that confer resistance to hormonal therapy in patients with breast cancer and that co-targeting such alterations alongside ER could prevent or delay the emergence of drug-resistant clones. Three specific aims are proposed. In Aim 1, paired tumor samples and cfDNA collected from breast cancer patients before and during treatment and at the time of disease progression on hormonal therapy will be used to define the landscape and timing of molecular changes that arise under the selective pressure of therapy. Our preliminary data indicate that ERBB2 mutation is a mechanism of both intrinsic and acquired resistance to hormonal therapy. We have also found that the HER kinase inhibitor neratinib can induce profound therapeutic responses that are limited by the induction of ER activity and consequent emergence of drug resistance. Thus, in Aim 2, we will use paired pretreatment and disease-progression tumor biopsies, cfDNA collected at regular intervals during treatment with neratinib alone or with the ER degrader fulvestrant, and engineered isogenic models and patient-derived xenografts to identify and validate mechanisms of resistance to these therapeutic agents. Finally, our genomic analysis identified RAS/ERK pathway alterations in ~10% of tumors collected following disease progression on hormonal therapy. In Aim 3, we will explore the functional significance of this finding and seek to develop therapeutic strategies for overcoming hormonal therapy resistance in this molecularly defined population. The long-term objective of this project is to develop therapeutic strategies for ER+ breast cancer guided by real-time, non-invasive molecular monitoring of tumor evolution. The work proposed will also generate valuable preclinical models of HER2-mutant and NF1-mutant ER+ breast cancer that can be used in future studies to assess promising novel therapeutic approaches for these molecularly defined populations.