Novel protein kinase signaling associated with platinum resistance in ovarian cancer

与卵巢癌铂耐药相关的新型蛋白激酶信号传导

• 批准号: 10305342
• 负责人: SHUANG HUANG
• 金额: $ 44.3万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10305342
• 关键词: Apoptosis; Apoptotic; C-terminal; Cancer Patient; Cancer cell line; Cell Line; Cells; Cessation of life; Clinic; Cytotoxic agent; Data; Data Set; Databases; Defect; Development; Early Diagnosis; Event; Excision; Glean; Goals; In Vitro; Investigation; Knock-in; Knowledge; Laboratories; MAPK8 gene; MCL1 gene; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of ovary; Mediating; Mediator of activation protein; Minor; Molecular; N-terminal; Neurons; Outcome; Patients; Phosphorylation; Phosphotransferases; Platinum; Play; Protein Kinase; Proteins; Recurrence; Resistance; Role; Serous; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; Tyrosine; Ubiquitination; Work; aptamer; base; cancer cell; cancer recurrence; chemotherapy; data mining; drug repurposing; improved; in vivo Model; inhibitor/antagonist; insight; knock-down; mortality; novel; p53 Signaling Pathway; patient derived xenograft model; prevent; screening; success; therapeutic target

PROJECT SUMMARY Development of platinum resistance is one of the most important factors contributing to ovarian cancer recurrence and mortality. In our effort to decipher molecular mechanisms underlying platinum resistance, we performed a kinome-wide screening on platinum-resistant SK-OV3 ovarian cancer cell line and identified Src- Related Kinase Lacking C-Terminal Regulatory Tyrosine And N-Terminal Myristylation Sites (SRMS) as a top platinum resistance regulator. Further analysis of TCGA ovarian cancer dataset revealed that patients with high SRMS expression responded poorly to platinum-based therapy and had worse overall survival. Since knockdown of SRMS markedly sensitized p53-deficient ovarian cancer cell lines to platinum while only displayed minor effect on p53-competent cell lines, we reason that SRMS plays a critical role in platinum resistance of p53-deficient ovarian cancer. To glean the mechanistic insight into the role of SRMS in platinum resistance, we showed that SRMS prevents JNK activation, possibly by directly phosphorylating JNKs. JNK signaling pathway is well established as an essential mediator for apoptosis triggered by cytotoxic agents; our observation that SRMS is specifically involved in platinum resistance in p53-deficient cells suggests that 1) platinum induces apoptosis in p53-deficient ovarian cancer cells in a JNK signaling pathway-dependent manner because of the defect in p53 signaling pathway-mediated apoptosis; and 2) SRMS-led inhibition of JNK signaling alleviates platinum-induced apoptosis and thereby promotes platinum resistance in p53-deficient cells. p53 is uniformly deficient in high grade serous ovarian cancer (HGSOC). The discovery of SRMS’ prominent role in platinum resistance of p53- deficient cells indicates that SRMS can be an ideal therapeutic target against platinum resistance in HGSOC. In our “drug repurposing” screening, we found that PLX4720, a selective inhibitor of B-RafV600E, can potently inhibit SRMS activity. In this application, we propose 3 specific aims: 1) Characterize molecular mechanisms underlying SRMS-conferred platinum resistance; 2) Define platinum resistance-relevant events that are governed by SRMS-JNK signaling; and 3) Investigate the potential of targeting SRMS to augment efficacy of platinum therapy. The success of this application will uncover molecular mechanism underlying SRMS’ role in platinum resistance of ovarian cancer. Importantly, we will evaluate SRMS-targeted strategy to overcome platinum resistance in ovarian cancer.

项目概要 铂耐药性的发展是导致卵巢癌的最重要因素之一 复发和死亡率。在我们努力破译铂电阻潜在分子机制的过程中，我们 对铂耐药 SK-OV3 卵巢癌细胞系进行了全激酶组筛选，并鉴定了 Src- 缺少 C 末端调节酪氨酸和 N 末端肉豆蔻酰化位点 (SRMS) 的相关激酶作为顶部 铂电阻调节器。 TCGA 卵巢癌数据集的进一步分析显示，高卵巢癌患者 SRMS 表达对铂类治疗反应较差，总体生存率较差。自从击倒之后 的 SRMS 使 p53 缺陷的卵巢癌细胞系对铂显着敏感，但仅表现出轻微的效果 在 p53 感受态细胞系上，我们推断 SRMS 在 p53 缺陷的铂耐药性中发挥着关键作用 卵巢癌。为了深入了解 SRMS 在铂电阻中的作用，我们表明： SRMS 可能通过直接磷酸化 JNK 来阻止 JNK 激活。 JNK信号通路良好 被确定为细胞毒性剂引发的细胞凋亡的重要介质；我们观察到 SRMS 是 特别参与 p53 缺陷细胞的铂耐药性表明 1) 铂诱导细胞凋亡 由于 p53 缺陷，p53 缺陷的卵巢癌细胞以 JNK 信号通路依赖性方式 信号通路介导的细胞凋亡； 2) SRMS 主导的 JNK 信号传导抑制可减轻铂诱导的 细胞凋亡，从而促进 p53 缺陷细胞的铂耐药性。 p53 普遍缺乏高 级别浆液性卵巢癌（HGSOC）。 SRMS 在 p53- 铂耐药性中的突出作用的发现 缺陷细胞表明 SRMS 可以成为 HGSOC 铂耐药的理想治疗靶点。在 在我们的“药物再利用”筛选中，我们发现 PLX4720，一种 B-RafV600E 的选择性抑制剂，可以有效地 抑制SRMS活性。在此应用中，我们提出了 3 个具体目标：1）表征分子机制 底层 SRMS 赋予的铂电阻； 2) 定义与铂电阻相关的事件 由 SRMS-JNK 信号控制； 3) 研究以 SRMS 为靶点来增强药物疗效的潜力 铂类疗法。该应用的成功将揭示 SRMS 在以下方面发挥作用的分子机制： 卵巢癌铂类耐药。重要的是，我们将评估以 SRMS 为目标的策略来克服 卵巢癌的铂耐药性。