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.

项目摘要 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。为了努力破译铂耐药性的分子机制，我们 在耐铂SK-ov3卵巢癌细胞系上进行了整个范围的筛查，并确定了SRC- 缺乏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 铂抗性调节剂。 TCGA卵巢癌数据集的进一步分析表明，患者高 SRMS表达对基于铂的治疗的反应较差，并且总体生存率较差。自敲除 SRMS明显敏感的p53缺陷卵巢癌细胞系对铂，而仅显示较小的效果 在p53能力的细胞系上，我们认为SRM在p53缺乏性的铂耐药性中起关键作用 卵巢癌。为了了解SRM在铂耐药性中的作用的机理洞察力，我们表明 SRM可阻止JNK激活，通过直接磷酸化JNK。 JNK信号通路很好 作为细胞毒性剂触发的细胞凋亡的必不可少的介体；我们认为SRM是 特别参与p53缺陷细胞中铂耐药性的表明1）铂诱导凋亡 p53缺陷型卵巢癌细胞以JNK信号通路依赖性方式，因为p53缺陷 信号通路介导的凋亡； 2）SRMS主导的JNK信号抑制减轻了铂诱导的 细胞凋亡，从而促进p53缺陷细胞中的铂耐药性。 p53均匀缺乏高 等级浆液卵巢癌（HGSOC）。发现SRMS在p53-铂抗性中的重要作用 缺陷的细胞表明SRM可以是针对HGSOC中铂耐药性的理想治疗靶标。在 我们的“药物重新调整”筛选，我们发现PLX4720是B-RAFV600E的选择性抑制剂，可以潜在地 抑制SRMS活性。在此应用中，我们提出了3个特定目的：1）表征分子机制 基础SRMS会议的铂抗性； 2）定义与铂抗性相关的事件 由srms-jnk信号传导约束； 3）研究靶向SRM提高效率的潜力 铂疗法。该应用的成功将发现SRM在SRM中的作用的分子机制 卵巢癌的铂抗性。重要的是，我们将评估以SRMS为目标的策略来克服 卵巢癌的铂抗性。