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

靶向 MARK2-HDAC 信号传导以克服胰腺癌中的紫杉醇耐药性

• 批准号: 10707545
• 负责人: Jixin Dong
• 金额: $ 26.1万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707545
• 关键词: Affect; Affinity; Albumins; Animal Model; Animals; Binding; Biochemical; Cancer Etiology; Cells; Cellular biology; Cessation of life; Chemoresistance; Chromosomal Instability; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Data; Drug resistance; FDA approved; Genes; Genetic; Genetic Epistasis; Genetic Transcription; Goals; Growth; HDAC4 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Immune; Immunocompetent; In Vitro; KPC model; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Maps; Mediating; Metabolism; Methods; Microtubules; Mitotic; Molecular; Outcome; Paclitaxel; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Site; Phosphotransferases; Prognostic Marker; Proteins; Recurrence; Regulation; Resistance; Role; Serine; Signal Pathway; Signal Transduction; Survival Rate; Testing; Text; Therapeutic; Transcription Coactivator; Translating; Treatment outcome; Tubulin; United States; Vorinostat; antitumor agent; cancer cell; cancer therapy; cancer type; cell growth; chemotherapy; cytotoxicity; drug sensitivity; efficacy outcomes; gemcitabine; histone deacetylase 2; improved; in vivo; malignant breast neoplasm; mortality; nanoparticle; novel; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; patient derived xenograft model; patient response; pre-clinical; programs; response; therapeutic target; upstream kinase

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.

抽象文本 许多抗蛋白毒剂，例如紫杉醇（紫杉醇），已广泛用于治疗几种类型 癌症，包括乳腺癌，卵巢，肺和胰腺癌。尽管它们在癌症治疗中广泛使用，但 但是，患者反应是高度可变的，耐药性仍然是一个主要的临床问题。因此是 确定预后标记以预测患者反应并增强药物敏感性的必要性。 通过生化和基于细胞的范围范围的筛网，我们确定了Mark2（微管亲和力 - 调节激酶2）作为PDAC中紫杉醇化学敏感性的关键调节剂（胰管导管 腺癌细胞。我们表明，MARK2响应抗维蛋白化学治疗剂而被磷酸化。 我们进一步确定了相应的激酶和映射的磷酸化位点。 Mark2决定紫杉醇 PDAC细胞中的细胞毒性而不会影响正常条件下的生长。从机械上讲，我们的发现也 表明MARK2通过调节IIA级HDAC（组蛋白脱乙酰基酶）来控制紫杉醇化学敏度。 MARK2在紫杉醇治疗后直接磷酸化HDAC4。 Mark2磷酸化的HDAC4积极 调节YAP（与是相关的蛋白质）活性并控制YAP靶基因的表达 由紫杉醇诱导。 HDACS的抑制作用使PDAC细胞在体外和IN敏感 免疫能力动物。我们的假设是Mark2-HDACS轴充当治疗靶标 用于克服PDAC患者的紫杉醇耐药性。我们将通过三个特定目标检验中心假设。 目标1：确定Mark2对抗蛋白质化学治疗剂的作用和调节；目标2： 阐明Mark2的下游效应子和机制，以响应紫杉醇化学治疗剂；目的 3：靶向HDAC和丝氨酸代谢以克服PDAC中的紫杉醇耐药性。新的识别 由抗维蛋白药物触发的调节剂和/或信号通路将揭示机制 潜在的化学抗性。我们的研究表明，将HDAC抑制剂与抗蛋白毒素相结合（例如 紫杉醇将增强在治疗耐药和/或复发性PDAC患者方面的功效。