Discovering the role of YES1 in triple negative breast cancer

发现 YES1 在三阴性乳腺癌中的作用

• 批准号: 10746980
• 负责人: RUTH A. KERI
• 金额: $ 3.13万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10746980
• 关键词: Adhesions; Architecture; Automobile Driving; Biological Models; Breast Cancer Cell; Breast Cancer Patient; Cell Nucleus; Cell Survival; Chromosomal Instability; Collection; Coupled; Cytotoxic Chemotherapy; Data; Defect; Disease; Drug Targeting; ERBB2 gene; Ensure; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Estrogens; Event; Family; Family member; Functional disorder; Gamma-H2AX; Genome Stability; Genomic Instability; Genomics; Goals; Growth; Heat-Shock Proteins 70; Heterogeneity; Individual; Malignant Neoplasms; Mediating; Metastatic/Recurrent; Mitosis; Mitotic; Molecular; Molecular Chaperones; Nuclear; Oncogenic; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phosphotransferases; Play; Precision therapeutics; Process; Progesterone; Proliferating; Protein Tyrosine Kinase; Proteins; Receptor Signaling; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Toxic effect; Work; YES1 gene; cancer initiation; cell growth; cell motility; chemotherapy; differential expression; drug efficacy; expectation; extracellular; improved; inhibitor; innovation; insight; live cell imaging; malignant breast neoplasm; micronucleus; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; overexpression; patient derived xenograft model; receptor; receptor expression; refractory cancer; response; restoration; src-Family Kinases; survivorship; targeted treatment; taxane; therapeutic target; transcription factor; transcriptomics; triple-negative invasive breast carcinoma; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT SRC Family Kinases (SFKs) are a group of 9 non-receptor tyrosine kinases that mediate the effects of many extracellular and intracellular signaling pathways. While these proteins have often been considered to be functionally similar to SRC, the founding member of the family, it is now clear that they have non-redundant and unique activities. In cancer, these proteins are differentially expressed and their roles can even be antagonistic. This project launches from our discovery that one of these family members, YES1, is selectively overexpressed in Triple Negative Breast Cancer (TNBC), is associated with poor outcomes, and is necessary for sustained growth of TNBC cells. TNBC is a collection of highly aggressive diseases with limited therapeutic options primarily involving cytotoxic chemotherapy. While many patients initially respond to these treatments, resistance is common, resulting in poor patient outcomes. Thus, identifying vulnerabilities in this group of diseases is essential to yield approaches for improving survivorship. We propose that YES1 is one of these vulnerabilities. In preliminary data, we show that YES1 is essential for maintaining expression of Epidermal Growth Factor Receptor (EGFR) as well as ensuring mitotic fidelity. EGFR is a major driver of TNBC growth. When YES1 is depleted, EGFR is degraded and its signaling is lost. In addition, we report that YES1 silencing causes several nuclear defects including micro-, multi-, and dysmorphic nuclei indicating that YES1 is essential for accurate completion of mitosis. We hypothesize that these two functions of YES1 are essential for cellular viability in TNBC. Moreover, we propose that YES1 may be a useful therapeutic target to improve the efficacy of drugs targeting EGFR and mitosis. In Aim 1, we will determine how YES1 controls EGFR degradation and assess whether YES1 overexpression underlies resistance to EGFR inhibitors in TNBC. Aim 2 will focus on identifying specific events in mitosis that are impacted by YES1 and the mechanisms involved. It will also discern whether modulating YES1 can impact response to taxanes, mainstay chemotherapies for TNBC. Lastly, in Aim 3, we will determine if EGFR and YES1 participate in a feedforward loop that controls mitosis. This will involve interrogating the role of EGFR in mediating the effects of YES1 on mitosis and determining if EGFR is also an upstream regulator of YES1. Major innovations of this project include the identification of YES1 as a new oncogenic driver of TNBC, the discovery that YES1 and EGFR may control the genomic complexity that is associated with this disease, the therapeutic assessment of a novel inhibitor of YES1 in PDX models of TNBC, and the potential for improving the efficacy of EGFR inhibitors and taxanes in a disease that requires new therapeutic approaches to improve patient outcomes.

项目摘要/摘要 SRC家族激酶（SFK）是一组9种非受体酪氨酸激酶，其介导许多细胞因子的作用。 细胞外和细胞内信号通路。虽然这些蛋白质通常被认为是 在功能上类似于SRC，家庭的创始成员，现在很明显，他们有非冗余， 独特的活动。在癌症中，这些蛋白质是差异表达的，它们的作用甚至可以是拮抗性的。 这个项目从我们发现这些家族成员之一YES1选择性过表达开始， 在三阴性乳腺癌（TNBC）中，与不良结局相关，并且需要持续 TNBC细胞的生长。TNBC是一组高度侵袭性疾病，治疗选择有限 主要涉及细胞毒性化疗。虽然许多患者最初对这些治疗有反应， 是常见的，导致患者预后不良。因此，确定这类疾病的脆弱性是 这是提高生存率的关键。我们认为YES1是这些漏洞之一。 在初步数据中，我们表明YES 1对于维持表皮生长因子的表达是必不可少的。 受体（EGFR）以及确保有丝分裂保真度。EGFR是TNBC增长的主要驱动力。当YES1为 当EGFR耗尽时，EGFR被降解并且其信号传导丢失。此外，我们报告说，YES1沉默导致几个 核缺陷，包括微，多，和畸形核，表明YES1是必不可少的准确 完成有丝分裂。我们假设YES 1的这两种功能对于细胞存活是必需的， TNBC。此外，我们建议YES 1可能是一个有用的治疗靶点，以提高药物的疗效 靶向EGFR和有丝分裂。在目标1中，我们将确定YES 1如何控制EGFR降解并评估 YES1过表达是否是TNBC中EGFR抑制剂耐药性的基础。目标2将侧重于确定 有丝分裂中受YES1影响的特定事件及其相关机制。它还将辨别 调节YES 1可以影响对紫杉烷类的反应，紫杉烷类是TNBC的主要化疗。在目标3中，我们将 确定EGFR和YES1是否参与控制有丝分裂的前馈回路。这将涉及审问 EGFR在介导YES 1对有丝分裂的影响中的作用，并确定EGFR是否也是一种上游调节因子， YES1的调节器。该项目的主要创新包括鉴定YES1作为新的致癌驱动因子 在TNBC中，发现YES1和EGFR可能控制与此相关的基因组复杂性， 疾病，在TNBC的PDX模型中对YES 1的新型抑制剂的治疗评估，以及 改善EGFR抑制剂和紫杉烷类在需要新的治疗方法的疾病中的功效， 改善患者结果。