Targeting MARK2-HDAC signaling to overcome paclitaxel resistance in pancreatic cancer

摘要文本 许多抗微管蛋白剂，如紫杉醇（Taxol），已被广泛用于治疗几种类型的 包括乳腺癌卵巢癌肺癌和胰腺癌尽管它们广泛用于癌症治疗， 然而，患者反应是高度可变的，并且耐药性仍然是主要的临床问题。因此 这对于鉴定预后标志物以预测患者反应和增强药物敏感性至关重要。 通过生物化学和基于细胞的激酶组范围的筛选，我们鉴定了MARK 2（微管亲和力- 调节激酶2）作为PDAC（胰腺导管）中紫杉醇化学敏感性的关键调节剂 腺癌）细胞。我们发现MARK 2在抗微管蛋白化疗药物的作用下被磷酸化。 我们进一步鉴定了相应的激酶并绘制了磷酸化位点。MARK 2决定紫杉醇 PDAC细胞的细胞毒性，而不影响正常条件下的生长。从机制上讲，我们的发现也 表明MARK 2通过调节IIa类HDAC（组蛋白脱乙酰酶）来控制紫杉醇化学敏感性。 MARK 2在紫杉醇处理后直接磷酸化HDAC 4。MARK 2-磷酸化HDAC 4阳性 调控雅普（yes相关蛋白）活性并特异性控制雅普靶基因的表达 由Taxol诱导。抑制HDAC使PDAC细胞对紫杉醇治疗的体外和体内敏感性 免疫活性动物。我们的假设是MARK 2-HDACs轴作为治疗靶点发挥作用 用于克服PDAC患者的紫杉醇耐药性。我们将通过三个具体目标来检验我们的中心假设。 目的1：确定MARK 2在抗微管蛋白化疗药物应答中的作用和调节;目的2： 阐明MARK 2在紫杉醇化疗反应中的下游效应子及其作用机制;目的 3：靶向HDAC和丝氨酸代谢以克服PDAC中的紫杉醇抗性。查明新 调节和/或信号通路触发的抗微管蛋白药物将阐明的机制， 潜在的化学抗性。我们的研究表明，HDAC抑制剂与抗微管蛋白药物（例如， 紫杉醇）在治疗耐药性和/或复发性PDAC患者中将具有增强的功效。

Abstract Text Many antitubulin agents, such as paclitaxel (Taxol), have been used extensively for treatment of several types of cancer, including breast, ovarian, lung, and pancreatic 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. Through biochemical and cell-based kinome-wide screens, we identified MARK2 (microtubule affinity- regulating kinase 2) as a critical regulator for Taxol chemosensitivity in PDAC (pancreatic ductal adenocarcinoma) cells. We show that MARK2 is phosphorylated in response to antitubulin chemotherapeutics. We further identified the corresponding kinase and mapped phosphorylation sites. MARK2 determines Taxol cytotoxicity in PDAC cells without affecting growth under normal conditions. Mechanistically, our findings also suggest that MARK2 controls Taxol chemosensitivity by regulating class IIa HDACs (histone deacetylase). MARK2 directly phosphorylates HDAC4 upon Taxol treatment. MARK2-phosphorylated HDAC4 positively regulates YAP (yes-associated protein) activity and controls expression of YAP target genes specifically induced by Taxol. Inhibition of HDACs sensitizes PDAC cells to Taxol treatment in vitro and in immunocompetent animals. Our hypothesis is that the MARK2-HDACs axis functions as a therapeutic target for overcoming Taxol resistance in PDAC patients. We will test our central hypothesis by three specific aims. Aim 1: Determine the role and regulation of MARK2 in response to antitubulin chemotherapeutics; Aim 2: Elucidate the downstream effectors and mechanisms of MARK2 in response to Taxol chemotherapeutics; Aim 3: Targeting HDACs and serine metabolism to overcome Taxol resistance in PDAC. 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 HDAC inhibitors with antitubulin agents (e.g. Taxol) will have enhanced efficacy in treatment of drug-resistant and/or recurrent PDAC patients.