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

摘要文本 许多抗微管蛋白药物，如紫杉醇，已被广泛用于治疗 几种癌症，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和耐药的 仍然是一个主要的临床问题。因此，确定预后标志物以预测 患者的反应和提高药物敏感性。蛋白激酶R(PKR)发挥着重要的作用 在对病毒感染和肿瘤发生的先天性免疫反应中。PKR的生物学意义 在抗微管蛋白方面，化疗药物和潜在的机制尚未确定。穿过 基于PHOS标签的全基因组生化筛查，我们发现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的失活会产生抵抗力 卵巢癌细胞和乳腺癌细胞中的紫杉醇。PKR表达增强对紫杉醇的促进作用 体外和体内的细胞毒性。我们进一步发现了蛋白酪氨酸激酶受体上新的磷酸化位点 抗微管蛋白-有丝分裂停滞和正常有丝分裂。从机制上讲，我们的发现也表明 PKR通过调节Bcl2的表达调控紫杉醇的化疗敏感性。我们的假设是 PKR-Bcl2轴作为抗微管蛋白制剂的治疗靶点 化疗药物治疗耐药和/或复发患者。我们将测试我们的中央 假设有三个具体的目的。目的1：研究PKR在抗微管蛋白中的功能意义 体内化疗药物；目标2：确定抗微管蛋白药物如何调节PKR；目标3： 阐明PKR在抗微管蛋白化疗敏感性中的作用机制及其下游信号转导机制。这个 识别由抗微管蛋白药物触发的新的调节因子和/或信号通路将会消失 阐明化疗耐药的潜在机制。我们的研究表明，结合激酶 PKR或Bcl2抑制剂的激活剂(例如，在本申请中描述)(FDA批准) 联合应用抗微管蛋白药物可提高耐药和/或复发的治疗效果 病人。我们的发现还表明，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小管蛋白的反应 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.