Characterizing and Targeting ERBB2 Mutations in Invasive Lobular Carcinoma

项目摘要 虽然浸润性小叶癌（ILC）占乳腺癌的10-15%，但仍有许多工作要做。 了解了这种疾病的独特性与浸润性导管癌（IDC）相比，ILC 研究不足，具有独特的组织学，基因组学和临床特征。尽管存在重大差异， 雌激素受体阳性（ER+）ILC最有可能接受与ER+ IDC女性相同的治疗 但长期结果往往较差。 最近，Lee-Oesterreich实验室和其他人已经确定了ERBB 2突变在ILC中的富集， 国际数据公司称由于ILC的特征是CDH 1（E-cadherin）的缺失，我们的研究结果可能表明ILC与E-cadherin之间存在潜在的相互作用。 ERBB 2突变与CDH 1缺失之间的关系由于ERBB 2突变通常 在没有ERBB 2扩增的情况下发生，目前没有FDA批准的靶向ERBB 2的治疗方法 突变型ILC。一些临床试验已经报道了抗HER 2酪氨酸激酶抑制剂的有希望的功效， 包括来那替尼，用于ERBB 2突变型ILC患者。然而，对这些疗法的抵抗是不可避免的。在 为了确定最有效的联合治疗，这些复发性ERBB的功能作用2 ILC中的突变需要进一步研究。采用临床标本相结合，创新体外 模型和基于CRISPR的基因组编辑，我们的提案将确定ERBB 2突变在 从转移性乳腺癌患者的血浆样本中收集ctDNA，并研究这些细胞如何在乳腺癌患者中表达。 突变影响HER 2激活和下游信号传导途径，以及对HER 2的敏感性/耐药性。 可用的抗HER 2剂（目标1）。我们还将评估CDH 1基因敲除和重新表达对细胞凋亡的影响。 HER 2信号传导和降解，以了解CDH 1丢失和突变之间的合作 ERBB 2在ILC中的作用，并探索E-cadherin调节HER 2的潜在机制（目的2）。 这项研究和未来研究的结果将有助于告知临床医生和研究人员的机制，临床 正在进行的临床试验中复发性ERBB 2突变和补体结果的相关性和靶向性 确定ERBB 2突变型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.