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进步，但乳腺癌在2009年仍持续存在。 美国癌症相关死亡率最高，每年有4万多美国人死于癌症。 年表皮生长因子受体（EGFR）抑制剂已被批准作为靶向治疗的一些 包括肺癌和结肠直肠癌在内的癌症，但在乳腺癌方面取得的成功有限。理论上， EGFR被确定为乳腺癌治疗的目标，因为其表达水平与乳腺癌的治疗效果呈负相关。 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，在这方面， 在实践中，注意到只有一小部分患者对EGFR抑制剂治疗有阳性反应， 许多人对抑制剂产生了抗药性。幸运的是，目前的研究表明， 抗性可能归因于其它受体酪氨酸激酶的活性。通过我们自己的支持 初步数据，我们假设受体酪氨酸激酶样孤儿受体1（ROR 1）是一个主要的 可能通过激活雅普导致三阴性乳腺癌患者EGFR耐药 通路配体结合的ROR 1与HER 3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，ROR 1的表达和 HER 3磷酸化与乳腺癌患者的不利结果相关，并且敲除HER 3磷酸化基因。 ROR 1在临床前模型中抑制TNBC的转移。 我们的中心假设是ROR 1/HER 3触发的雅普通路的激活促进了远端细胞凋亡。 TNBC的转移和对EGFR靶向治疗的抗性。我们将根据以下假设来解决这个问题： 三个具体目标。在具体目标1中，我们将证明ROR 1/HER 3信号传导的功能作用。 转移性TNBC中的轴。在具体目标2中，我们将定义ROR 1的分子机制- 介导的信号通路来激活雅普靶转录程序。在具体目标3中，我们 确定靶向ROR 1/雅普联合EGFR抑制剂的临床前获益。 EGFR抑制剂治疗已成功实施到各种患者的护理计划中， 癌症类型。然而，EGFR抑制剂治疗对于TNBC患者仅略微成功。的 拟议的研究将调查针对ROR 1/雅普信号通路的有效性， 避免对EGFR抑制剂的耐药性，从而改善对广泛使用的抑制剂的反应。的 研究团队将依靠高通量测序、生物化学、分子生物学和异种移植小鼠 模型，以全面评估涉及EGFR和ROR 1/雅普的共靶向策略， 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.