Combinatorial Treatment Strategies to Counteract EGFR Resistance

项目摘要 尽管在早期发现和治疗选择方面有了显著的改善，但乳腺癌仍然存在 癌症相关死亡率居美国之首，夺走了40,000多名美国人的生命 年。表皮生长因子受体(EGFR)抑制剂已被批准为许多靶向治疗药物 癌症，包括肺癌和结直肠癌，但在乳腺癌方面取得的成功有限。从理论上讲， EGFR被确定为乳腺癌治疗的感兴趣的靶点，因为它的表达水平是负的 与乳腺癌患者的预后相关，并且在许多乳腺癌病例中高度表达。然而， 在实践中，人们注意到只有一小部分患者对EGFR抑制剂治疗有积极反应， 许多人对这些抑制剂产生了抗药性。幸运的是，目前的研究表明这一点 抗性可能归因于其他受体酪氨酸激酶的活性。通过我们自己的支持 初步数据推测，受体酪氨酸激酶样孤儿受体1(ROR1)是主要的 三阴性乳腺癌患者EGFR耐药的因素，可能通过激活YAP 路径。配体结合的ROR1与HER3结合以触发先前未识别的信号级联， 导致YAP-靶转录程序的激活。此外，ROR1的表达和血管紧张素转换酶状态 HER3磷酸化与乳腺癌患者的不良预后相关，并且敲除 在临床前模型中，ROR1可抑制TNBC的转移。 我们的中心假设是，ROR1/HER3触发的YAP通路的激活促进了远端 肿瘤转移与EGFR靶向治疗耐药我们将根据 遵循三个具体目标。在特定的目标1中，我们将演示ROR1/HER3信号的功能作用 转移性TNBC的轴心。在具体目标2中，我们将定义支持ROR1的分子机制- 介导信号通路激活YAP靶标转录程序。在具体目标3中，我们将 确定靶向ROR1/YAP与EGFR抑制剂联合应用的临床前益处。 EGFR抑制剂治疗已成功落实到各种不同疾病患者的护理计划中 癌症类型。然而，对TNBC患者来说，EGFR抑制剂的治疗只是略微成功。这个 拟议的研究将调查靶向ROR1/YAP信号通路在 规避对EGFR抑制剂的耐药性，从而改善对广泛使用的抑制剂的反应。这个 研究小组将依靠高通量测序、生物化学、分子生物学和异种移植小鼠 全面评估涉及EGFR和ROR1/YAP的共同目标战略的模型，以帮助提供 TNBC患者成功治疗方法的科学基础。

Project Summary Despite notable improvements in early detection and therapeutic options, breast cancer has persisted in leading the United States in cancer related mortalities, taking the lives of more than 40,000 Americans each year. Epidermal growth factor receptor (EGFR) inhibitors have been approved as targeted therapies for a number of cancers, which include lung and colorectal cancers, but have seen limited success for breast cancer. In theory, EGFR was identified as a target of interest for breast cancer therapy because its expression levels are negatively correlated with breast cancer patient outcomes and it is highly expressed in many breast cancer cases. However, in practice, it was noted that only a small fraction of patients responded positively to EGFR inhibitor treatment, with many developing resistance to the inhibitors. Fortunately, current research efforts have revealed that this resistance may be attributed to the activity of other receptor tyrosine kinases. Through the support of our own preliminary data, we hypothesize that receptor tyrosine kinase-like orphan receptor 1 (ROR1) is one of the major contributors to EGFR resistance in triple-negative breast cancer patients, likely through activation of YAP pathway. The ligand-bound ROR1 associates with HER3 to trigger previous unidentified signaling cascades, leading to activation of YAP-target transcriptional program. Additionally, the expression of ROR1 and status of HER3 phosphorylation are correlated with unfavorable outcomes for breast cancer patients, and knock out of ROR1 inhibited metastasis of TNBC in preclinical models. Our central hypothesis is that ROR1/HER3-triggered activation of the YAP pathway promotes distal metastasis of TNBC and resistance to EGFR-target therapy. We will address this hypothesis according to the following 3 specific aims. In Specific Aim 1, we will demonstrate the functional role of the ROR1/HER3 signaling axis in metastatic TNBC. In Specific Aim 2, we will define the molecular mechanism that underlies the ROR1- mediated signaling pathway to activate the YAP target transcriptional program. In Specific Aim 3, we will determine the preclinical benefits of targeting ROR1/YAP in combination with EGFR inhibitors. EGFR inhibitor treatment has been successfully implemented into the care plans of patients with a variety of cancer types. However, EGFR inhibitor treatment has only been marginally successful for TNBC patients. The proposed research will investigate the effectiveness of targeting the ROR1/YAP signaling pathway in circumventing resistance to EGFR inhibitors and thus improving response to the widely used inhibitors. The research team will rely on high-throughput sequencing, biochemistry, molecular biology, and xenograft mouse models to comprehensively assess a co-targeting strategy that involves EGFR and ROR1/YAP to help provide the scientific basis for a successful treatment approach for patients with TNBC.