Targeting PKR-Bcl2 Signaling to Overcome Paclitaxel Resistance in Ovarian Cancer

靶向 PKR-Bcl2 信号传导以克服卵巢癌中的紫杉醇耐药性

• 批准号: 10502982
• 负责人: Jixin Dong
• 金额: $ 41.34万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10502982
• 关键词: Affect; Agonist; Animal Model; Apoptotic; BCL2 gene; Biochemical; Biological; Biological Markers; Breast Cancer Cell; Cancer Cell Growth; Cancer Patient; Cell Death; Cells; Cellular Metabolic Process; Cellular Stress; Chemoresistance; Clinic; Clinical; Clinical Trials; DNA Damage; Data; Double-Stranded RNA; Drug resistance; Eukaryotic Initiation Factors; FDA approved; Family; Human; Immune response; Immunocompetent; In Vitro; Innate Immune Response; Interferons; Knowledge; Light; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mediating; Messenger RNA; Metabolism; Microtubules; Mitosis; Mitotic; Molecular; Molecular Target; Multi-Drug Resistance; Outcome; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Prognostic Marker; Prokaryotic Initiation Factor-2; Protein Kinase; Proteins; Recurrence; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Protein; Stress; Testing; Text; Transcriptional Regulation; Translating; Validation; Virus Diseases; antitumor agent; base; cancer cell; cancer therapy; cancer type; cytokine; cytotoxicity; drug sensitivity; improved; in vivo; inhibitor; malignant breast neoplasm; new therapeutic target; novel; patient response; pre-clinical; protein expression; protein function; protein kinase R; protein profiling; response; therapeutic target; tumor; tumorigenesis

Abstract Text Many antitubulin agents, such as paclitaxel (Taxol), have been used extensively for treatment of several types of cancer, including ovarian, lung, pancreatic, and breast cancers. Despite their wide use in cancer treatment, however, patient response is highly variable and drug resistance remains a major clinical issue. It is therefore essential to identify prognostic markers to predict the patient response and to enhance drug sensitivity. Protein kinase R (PKR) plays significant roles in innate immune response to viral infection and tumorigenesis. The biological significance of PKR in antitubulin chemotherapeutics and underlying mechanisms have yet to be defined. Through Phos-tag-based kinome-wide biochemical screens, we identified PKR as a critical regulator in antitubulin cytotoxicity. Our preliminary data suggest that inactivation of PKR confers resistance to Taxol in ovarian and breast cancer cells. Enhanced expression of PKR potentiates taxol cytotoxicity in vitro and in vivo. We further identified novel phosphorylation sites on PKR during antitubulin-mitotic arrest and in normal mitosis. Mechanistically, our findings also suggest that PKR controls Taxol chemosensitivity through modulating Bcl2 expression. Our hypothesis is that the PKR-Bcl2 axis functions as a therapeutic target for antitubulin agent-based chemotherapeutics in treatment of drug-resistant and/or recurrent patients. We will test our central hypothesis by three specific aims. Aim 1: Examine the functional significance of PKR in antitubulin chemotherapeutics in vivo; Aim 2: Determine how antitubulin drugs regulate PKR; Aim 3: Elucidate the mechanisms and downstream signaling of PKR in antitubulin chemosensitivity. The identification of new regulators and/or signaling pathways triggered by antitubulin drugs will shed light on the mechanisms underlying chemoresistance. Our study suggests that combining kinase activators (e.g., being characterized in this application) for PKR or Bcl2 inhibitors (FDA-approved) with antitubulin agents will have enhanced efficacy in treatment of drug-resistant and/or recurrent patients. Our findings also suggest that profiling PKR-Bcl2 signaling status of tumors (mRNA/protein levels and activity) can be useful to predict the patient response to antitubulin chemotherapeutics.

抽象文本 许多抗微管蛋白药物，例如紫杉醇（Taxol），已被广泛用于治疗 多种癌症，包括卵巢癌、肺癌、胰腺癌和乳腺癌。尽管他们的 在癌症治疗中广泛使用，然而，患者的反应变化很大并且耐药性 仍然是一个主要的临床问题。因此，有必要确定预后标志物来预测 患者反应并增强药物敏感性。蛋白激酶 R (PKR) 发挥重要作用 对病毒感染和肿瘤发生的先天免疫反应。 PKR的生物学意义 抗微管蛋白化疗药物中的作用和潜在机制尚未明确。通过 基于磷酸标签的激酶组范围的生化筛选，我们确定 PKR 是 抗微管蛋白细胞毒性。我们的初步数据表明 PKR 失活会产生耐药性 卵巢癌细胞和乳腺癌细胞中的紫杉醇。 PKR 表达增强可增强紫杉醇 体外和体内细胞毒性。我们进一步鉴定了 PKR 上的新磷酸化位点 抗微管蛋白有丝分裂停滞和正常有丝分裂。从机制上讲，我们的研究结果还表明 PKR 通过调节 Bcl2 表达来控制紫杉醇的化学敏感性。我们的假设是 PKR-Bcl2 轴作为基于抗微管蛋白药物的治疗靶点 用于治疗耐药和/或复发患者的化疗药物。我们将测试我们的中央 三个具体目标的假设。目标 1：检查 PKR 在抗微管蛋白中的功能意义 体内化疗；目标 2：确定抗微管蛋白药物如何调节 PKR；目标 3： 阐明 PKR 在抗微管蛋白化学敏感性中的机制和下游信号传导。这 抗微管蛋白药物触发的新调节因子和/或信号通路的鉴定将会脱落 阐明化学耐药性的潜在机制。我们的研究表明结合激酶 PKR 或 Bcl2 抑制剂（FDA 批准）的激活剂（例如，在本申请中进行表征） 与抗微管蛋白药物联合使用可增强治疗耐药性和/或复发性的疗效 患者。我们的研究结果还表明，分析肿瘤的 PKR-Bcl2 信号状态 （mRNA/蛋白质水平和活性）可用于预测患者对抗微管蛋白的反应 化疗。