Characterizing and Targeting ERBB2 Mutations in Invasive Lobular Carcinoma

项目总结 尽管浸润性小叶癌(ILC)占乳腺癌的10%-15%，但仍有许多问题有待解决 了解了这种疾病的独特性质。与浸润性导管癌(IDC)相比，ILC是 未被研究，具有明显的组织学、基因组和临床特征。尽管存在重大差异，但女性 对于雌激素受体阳性(ER+)的ILC，很可能会接受与ER+IDC女性相同的治疗 尽管往往表现出较差的长期结果。 最近，Lee-Oester reich实验室和其他实验室通过比较发现ILC中ERBB2突变的丰富 致国际数据公司。由于ILC的特征是CDH1(E-钙粘附素)的丢失，我们的发现可能暗示了一种潜在的相互作用 CDH1缺失和ERBB2突变在推动ILC肿瘤进展中的作用。因为ERBB2突变通常 在没有ERBB2扩增的情况下发生，目前还没有FDA批准的针对ERBB2的治疗 突变体ILC。几项临床试验报告了抗HER2酪氨酸激酶抑制剂的良好疗效， 包括奈拉替尼，用于ERBB2突变ILC患者。然而，对这些疗法的抵抗是不可避免的。在……里面 为了确定最有效的联合疗法，这些复发的ERBB2的功能作用 ILC的突变需要进一步研究。结合临床标本，在体外进行创新 模型和基于CRISPR的基因组编辑，我们的建议将确定ERBB2突变在 从转移性乳腺癌患者的血浆样本中收集ctDNA，并研究这些 突变影响HER2激活和下游信号通路以及对 现有的抗HER2药物(目标1)。我们还将评估CDH1基因敲除和重新表达对 HER2信号与降解，以了解CDH1缺失和突变之间的协同作用 在ILC的ERBB2中，并探索E-钙粘素调节HER2的潜在机制(目标2)。 这项研究和未来的研究结果将有助于临床医生和研究人员了解其发病机制，临床 正在进行的临床试验中复发的ERBB2突变和补体发现的相关性和靶向性 目的：确定ERBB2基因突变ILC患者最有效的治疗组合。

PROJECT SUMMARY Although invasive lobular carcinoma (ILC) accounts for 10-15% of breast cancer, there remains much to be learned about the unique nature of this disease. Compared to invasive ductal carcinoma (IDC), ILC is understudied, with distinct histological, genomic, and clinical characteristics. Despite key differences, women with estrogen receptor-positive (ER+) ILC will most likely receive the same treatment as women with ER+ IDC though often show inferior long-term outcomes. Recently, the Lee-Oesterreich Lab and others have identified enrichment of ERBB2 mutations in ILC compared to IDC. As ILC is characterized by loss of CDH1 (E-cadherin), our findings may suggest a potential interaction between loss of CDH1 and mutations in ERBB2 in driving ILC tumor progression. As ERBB2 mutations usually occur in the absence of ERBB2 amplification, there are currently no FDA-approved therapies targeting ERBB2 mutant ILC. Several clinical trials have reported promising efficacy of anti-HER2 tyrosine kinase inhibitors, including neratinib, in patients with ERBB2 mutant ILC. However, resistance to these therapies is inevitable. In order to identify the most effective combination therapies, the functional role of these recurrent ERBB2 mutations in ILC requires further investigation. Using a combination of clinical specimens, innovative in vitro models and CRISPR-based genome editing, our proposal will determine the prevalence of ERBB2 mutations in ctDNA collected from plasma samples of patients with metastatic breast cancer and investigate how these mutations influence HER2 activation and downstream signaling pathways and sensitivity/resistance to available anti-HER2 agents (Aim 1). We will also evaluate the effects of CDH1 knockout and re-expression on HER2 signaling and degradation in order to understand the cooperation between loss of CDH1 and mutations in ERBB2 in ILC and explore potential mechanisms of HER2 regulation by E-cadherin (Aim 2). Results of this and future research will help inform clinicians and researchers of the mechanisms, clinical relevance, and targetability of recurrent ERBB2 mutations and complement findings from ongoing clinical trials to identify the most effective therapy combinations for patients with ERBB2 mutant ILC.