FGFR4: A druggable mediator of endocrine resistance in breast cancer

每年约有30，000例新诊断的浸润性小叶乳腺癌（ILC）病例使ILC成为第六常见的乳腺癌。 女性的癌症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-钙粘蛋白丢失。虽然 ILC显示出比IDC更好的预后标志物，例如雌激素受体（ER）阳性率高， ILC患者通常会对内分泌治疗产生耐药性，从长远来看， 比IDC更快。我们的长期目标是改善ILC患者的预后， 其理解有限并且代表了巨大的未满足的临床需求。 为了了解ILC内分泌抵抗的机制，我们建立了内分泌抵抗的ILC细胞系， 模型，并收集内分泌耐药转移性乳腺癌样本，和无偏转录组学 分析导致成纤维细胞生长因子受体4（FGFR 4）被鉴定为最过度表达的 基因对公开可用数据库的分析导致热点FGFR 4突变的鉴定。缺乏 FGFR 1 -3在内分泌抵抗模型和转移组织中的一致过表达强烈提示 FGFR 4的独特和以前未被认识到的作用值得进一步研究。而FGFR 4 尽管在IDC和ILC中都观察到过表达和突变，但它们在ILC中显著富集。这 这表明ILC独特的遗传背景，包括众所周知的E-钙粘蛋白的丢失， 最近发现的ERBB 2/ERBB 3的激活可能为FGFR 4提供了一个允许的环境， 发信号。在功能上，FGFR 4缺失或抑制导致ER靶基因的表达改变， 生长和菌落形成减少。最后，结合FGFR 4和ER靶向的初步研究 赋予协同生长抑制。因此，我们假设ILC独特的遗传背景 为FGFR 4信号传导介导内分泌抗性创造了一个允许的环境， FGFR 4抑制和内分泌疗法的组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FGFR 4如何导致乳腺癌的内分泌抵抗，和ii） 检查原发性和转移性乳腺癌的关键基因组特征是否会相互影响， FGFR 4信号传导和活性，和iii）通过以下步骤证明FGFR 4作为乳腺癌治疗中的可药物化靶标： 定义生物标志物。 我们的合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，有价值的临床样本，已经在试验中的有前途的药物， 创新的方法和工具来测试我们对FGFR 4在内分泌中的新作用的重点假设 阻力我们期望获得关于容易药物化的ER-FGFR 4轴如何在细胞中信号传导的基础知识。 ILC和！评估FGFR 4抑制作为内分泌耐药乳腺癌的新型治疗策略。 !

~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. !