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: 10550218
• 负责人: RUTH A. KERI
• 金额: $ 45.21万
• 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/10550218
• 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个非受体酪氨酸激酶，它们介导许多 细胞外和细胞内的信号通路。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，他们有非冗余和 独特的活动。在癌症中，这些蛋白质的表达是不同的，它们的作用甚至可以是拮抗的。 这个项目是从我们发现这些家族成员中的一个，YES1，选择性过度表达开始的 在三阴性乳腺癌(TNBC)中，与不良预后相关，并且是持续的必要条件 TNBC细胞的生长情况。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，但耐药性 是很常见的，导致患者预后不佳。因此，识别这组疾病中的脆弱性是 是提高生存能力的关键。我们认为YES1就是这些漏洞之一。 在初步数据中，我们发现YES1对于维持表皮生长因子的表达是必不可少的 受体(EGFR)以及确保有丝分裂的保真度。EGFR是TNBC增长的主要驱动力。当YES1为 一旦耗尽，EGFR就会降解，其信号也会丢失。此外，我们报告了YES1沉默导致几个 包括微核、多形核和异形核在内的核缺陷表明YES1对于 有丝分裂完成。我们假设YES1的这两个功能是细胞存活所必需的。 TNBC。此外，我们认为YES1可能是提高药物疗效的一个有用的治疗靶点。 靶向EGFR和有丝分裂。在目标1中，我们将确定YES1如何控制EGFR的降解并评估 YES1过表达是否是TNBC对EGFR抑制剂耐药的基础。目标2将专注于识别 有丝分裂中受YES1影响的特定事件及其相关机制。它还将辨别是否 调节YES1可以影响对紫杉烷类药物的反应，紫杉烷是TNBC的主要化疗药物。最后，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环路。这将涉及到审问 EGFR在介导YES1对有丝分裂的影响及确定EGFR是否也是上游的作用 YES1的调节器。该项目的主要创新包括将YES1确定为新的致癌驱动因素 发现YES1和EGFR可能控制与此相关的基因组复杂性 一种新的YES1抑制剂在PDX TNBC模型中的疗效评估，以及 提高EGFR抑制剂和紫杉烷类药物在需要新的治疗方法的疾病中的疗效 改善患者的预后。