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

摘要文本 许多抗微管蛋白剂，如紫杉醇（Taxol），已广泛用于治疗 几种类型的癌症，包括卵巢癌、肺癌、胰腺癌和乳腺癌。尽管他们 然而，在癌症治疗中广泛使用，患者的反应是高度可变的，并且耐药性 仍然是一个主要的临床问题。因此，识别预后标志物以预测 患者反应和增强药物敏感性。蛋白激酶R（PKR）在肿瘤的发生发展中起着重要的作用 在对病毒感染和肿瘤发生的先天免疫反应中。PKR的生物学意义 在抗微管蛋白化疗药物和潜在的机制尚未确定。通过 通过基于Phos标签的激酶组范围的生化筛选，我们确定PKR是一个关键的调节因子， 抗微管蛋白细胞毒性。我们的初步数据表明，PKR的失活赋予耐药 卵巢癌和乳腺癌细胞中的紫杉醇。PKR表达增强增强紫杉醇活性 体外和体内细胞毒性。我们进一步鉴定了PKR上新的磷酸化位点， 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Bcl 2表达控制紫杉醇化疗敏感性。我们的假设是 PKR-Bcl 2轴作为基于抗微管蛋白药物的治疗靶点发挥作用 在治疗耐药和/或复发患者中的化学治疗剂。我们将测试我们的中央 三个具体目标的假设。目的1：研究PKR在抗微管蛋白中的功能意义 目的2：确定抗微管蛋白药物如何调节PKR;目的3： 阐明PKR在抗微管蛋白药物敏感性中的作用机制及其下游信号通路。的 识别由抗微管蛋白药物触发的新调节剂和/或信号通路将有助于 化学抗性的潜在机制。我们的研究表明结合激酶 活化剂（例如，在本申请中表征）用于PKR或Bcl 2抑制剂（FDA批准的） 与抗微管蛋白剂联合使用将在治疗耐药性和/或复发性 患者我们的研究结果还表明，分析PKR-Bcl 2信号状态的肿瘤 (mRNA/蛋白水平和活性）可用于预测患者对抗微管蛋白的反应 化疗药物

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.