FGFR4: A druggable mediator of endocrine resistance in breast cancer

每年约30,000例新诊断的浸润性小叶乳腺癌(ILC)使浸润性小叶乳腺癌在最常见的乳腺癌中排名第六 女性患癌症。ILC的治疗几乎与更常见的浸润性导管癌(IDC)相同，尽管 临床表现和肿瘤生物学的差异，包括几乎普遍的E-钙粘附素丢失。虽然 ILC显示出比IDC更好的预后标志，如雌激素受体(ER)阳性率高和低 增殖，ILC患者经常对内分泌治疗产生抵抗力，长期来看 复发率高于IDC。我们的长期目标是改善ILC患者的预后，ILC是一种相关疾病 有限的理解，代表着巨大的未得到满足的临床需求。 为了了解ILC内分泌耐药的机制，我们建立了内分泌耐药的ILC细胞系。 模型，并收集内分泌抵抗的转移性乳腺癌样本，并无偏见地转录 结果表明，成纤维细胞生长因子受体4(FGFR4)是最高表达的 吉恩。对公开可用的数据库的分析导致鉴定热点FGFR4突变。缺乏 FGFR1-3在内分泌耐药模型和转移组织中的持续过表达强烈提示 FGFR4的一个独特的、以前没有被认识到的作用值得进一步研究。而FGFR4 在IDC和ILC中均可观察到过表达和突变，ILC显著丰富。这 提示ILC的独特遗传背景，包括众所周知的E-钙粘蛋白丢失，以及 最近发现的ERBB2/ERBB3的激活可能为FGFR4提供了一个允许的环境 发信号。在功能上，FGFR4的缺失或抑制会导致ER靶基因和 生长和菌落形成减少。FGFR4和ER联合靶向的初步研究 协同抑制生长。因此，我们假设ILC的独特遗传背景 为FGFR4信号调节内分泌抵抗创造了一个允许的环境，并且 FGFR4抑制和内分泌治疗的结合代表了一种新的治疗策略。 在目前的研究中，我们将i)确定FGFR4如何在乳腺癌中引起内分泌抵抗，以及ii) 检查原发癌和转移性乳腺癌的关键基因组特征是否相互干扰并增强 FGFR4信号和活性，以及iii)通过以下方式证明FGFR4是乳腺癌治疗的可用药靶点 定义生物标志物。 我们的协作团队拥有分子生物学、生物统计学/生物信息学、病理学和医学方面的专业知识 肿瘤学将利用独特的模型、宝贵的临床样本、已经在试验中的有希望的药物，以及 创新的方法和工具来测试我们关于FGFR4在内分泌中的新作用的重点假说 抵抗。我们期望获得关于容易下药的ER-FGFR4轴是如何在 ILC和！评估抑制FGFR4作为内分泌抵抗乳腺癌的一种新的治疗策略。 好了！

~30,000 new cases of invasive lobular breast cancer (ILC) diagnosed per year make ILC the 6th most common cancer in women. ILC is treated almost identically to the more common invasive ductal cancer (IDC), despite differences in clinical presentation and tumor biology, including the near universal loss of E-cadherin. Although ILCs show better prognostic markers than IDC, such as high rates of estrogen receptor (ER) positivity and low proliferation, patients with ILC often develop resistance to endocrine therapy and in the long term suffer more recurrences than IDC. Our long-term goal is to improve outcome for patients with ILC, a disease associated with limited understanding and representing a great unmet clinical need. To understand mechanisms driving ILC endocrine resistance, we developed endocrine-resistant ILC cell line models, and collected endocrine resistant metastatic breast cancer samples, and unbiased transcriptomic profiling led to the identification of fibroblast growth factor receptor 4 (FGFR4) as the most overexpressed gene. Analysis of publicly available databases lead to identification of hotspot FGFR4 mutations. Lack of consistent overexpression of FGFR1-3 in endocrine resistant models and metastatic tissues strongly suggests a unique and previously unappreciated role for FGFR4 that warrants further study. While FGFR4 overexpression and mutations are observed in both IDC and ILC, they are significantly enriched in ILC. This suggests that the unique genetic background of ILC, including the well-known loss of E-cadherin but also the more recently identified activation of ERBB2/ERBB3, may provide a permissive environment for FGFR4 signaling. Functionally, FGFR4 loss or inhibition results in altered expression of ER target genes and decreased growth and colony formation. Finally, preliminary studies of combined FGFR4 and ER targeting confer synergistic growth inhibition. We therefore hypothesize that the unique genetic background of ILC creates a permissive environment for FGFR4 signaling to mediate endocrine resistance, and that the combination of FGFR4 inhibition and endocrine therapy represents a novel treatment strategy. In the current study, we will i) determine how FGFR4 causes endocrine resistance in breast cancer, and ii) examine whether key genomic features of primary and metastatic breast cancer cross-talk and enhance FGFR4 signaling and activity, and iii) credential FGFR4 as a druggable target in breast cancer therapy by defining biomarkers. Our collaborative team with expertise in molecular biology, biostatistics/bioinformatics, pathology and medical oncology will utilize unique models, valuable clinical samples, promising drugs that are already in trials, and innovative approaches and tools to test our focused hypotheses on a novel role of FGFR4 in endocrine resistance. We expect to gain fundamental knowledge of how the readily druggable ER-FGFR4 axis signals in ILC and!to assess FGFR4 inhibition as a novel treatment strategy in endocrine resistant breast cancers. !