FGFR4: A druggable mediator of endocrine resistance in breast cancer

每年诊断出约 30,000 例新诊断的浸润性小叶乳腺癌 (ILC) 病例，使 ILC 成为第六大常见病例 女性癌症。 ILC 的治疗方法与更常见的浸润性导管癌 (IDC) 几乎相同，尽管 临床表现和肿瘤生物学的差异，包括 E-钙粘蛋白几乎普遍缺失。虽然 ILC 显示出比 IDC 更好的预后标志物，例如雌激素受体 (ER) 阳性率高和雌激素受体 (ER) 阳性率低 增殖，ILC 患者常常对内分泌治疗产生耐药性，从长远来看，会遭受更多的痛苦 复发率高于 IDC。我们的长期目标是改善 ILC（一种与 ILC 相关的疾病）患者的治疗结果 理解有限，代表着巨大的未满足的临床需求。 为了了解驱动 ILC 内分泌抵抗的机制，我们开发了内分泌抵抗 ILC 细胞系 模型，并收集内分泌抵抗性转移性乳腺癌样本，并进行无偏转录组学分析 分析发现成纤维细胞生长因子受体 4 (FGFR4) 是最过度表达的 基因。对公开数据库的分析可识别 FGFR4 热点突变。缺乏 FGFR1-3 在内分泌抵抗模型和转移组织中一致过度表达强烈表明 FGFR4 具有独特且之前未被重视的作用，值得进一步研究。而 FGFR4 在 IDC 和 ILC 中均观察到过表达和突变，并且它们在 ILC 中显着富集。这个 表明 ILC 的独特遗传背景，包括众所周知的 E-钙粘蛋白丢失，但也包括 最近发现的 ERBB2/ERBB3 激活可能为 FGFR4 提供宽松的环境 发信号。从功能上来说，FGFR4 缺失或抑制会导致 ER 靶基因的表达改变， 生长和集落形成减少。最后，FGFR4和ER联合靶向的初步研究 具有协同生长抑制作用。因此，我们假设 ILC 的独特遗传背景 为 FGFR4 信号传导介导内分泌抵抗创造了一个宽松的环境，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。 在当前的研究中，我们将 i) 确定 FGFR4 如何导致乳腺癌内分泌抵抗，以及 ii) 检查原发性和转移性乳腺癌的关键基因组特征是否相互影响并增强 FGFR4 信号传导和活性，以及 iii) 证明 FGFR4 作为乳腺癌治疗中的药物靶标 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、有价值的临床样本、已经在试验中的有前途的药物，以及 创新方法和工具来测试我们对 FGFR4 在内分泌中的新作用的集中假设 阻力。我们期望获得关于易于药物化的 ER-FGFR4 轴如何在体内发出信号的基础知识 ILC 并评估 FGFR4 抑制作为内分泌抵抗性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. !