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: 10518249
• 负责人: Jixin Dong
• 金额: $ 33.23万
• 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/10518249
• 关键词: Affect; Affinity; Albumins; Animal Model; Animals; Biochemical; Cancer Etiology; Cells; Cellular biology; Cessation of life; Chemoresistance; Chromosomal Instability; Clinic; Clinical; Clinical Trials; 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; Light; 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; United States; Vorinostat; antitumor agent; base; cancer cell; cancer therapy; cancer type; cell growth; chemotherapy; cytotoxicity; drug sensitivity; efficacy outcomes; gemcitabine; 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 许多抗微管蛋白药物，例如紫杉醇（Taxol），已广泛用于治疗多种类型的疾病 癌症，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，患者的反应差异很大，耐药性仍然是一个主要的临床问题。因此是 对于识别预后标志物以预测患者反应和增强药物敏感性至关重要。 通过生化和基于细胞的激酶组范围筛选，我们鉴定了 MARK2（微管亲和力- 调节激酶 2) 作为 PDAC（胰导管）紫杉醇化学敏感性的关键调节因子 腺癌）细胞。我们发现 MARK2 因抗微管蛋白化疗药物而被磷酸化。 我们进一步鉴定了相应的激酶并绘制了磷酸化位点。 MARK2 测定紫杉醇 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，我们的发现还 表明 MARK2 通过调节 IIa 类 HDAC（组蛋白脱乙酰酶）来控制紫杉醇的化学敏感性。 MARK2 在紫杉醇处理后直接磷酸化 HDAC4。 MARK2 磷酸化 HDAC4 阳性 调节 YAP（yes 相关蛋白）活性并特异性控制 YAP 靶基因的表达 由紫杉醇诱导。 HDAC 的抑制使 PDAC 细胞在体外和体内对紫杉醇治疗敏感 免疫能力强的动物。我们的假设是 MARK2-HDAC 轴作为治疗靶点 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。 目标 1：确定 MARK2 在抗微管蛋白化疗药物反应中的作用和调节；目标 2： 阐明MARK2响应紫杉醇化疗药物的下游效应子和机制；目的 图 3：靶向 HDAC 和丝氨酸代谢以克服 PDAC 中的紫杉醇耐药性。新的鉴定 抗微管蛋白药物触发的调节因子和/或信号通路将揭示其机制 潜在的化学耐药性。我们的研究表明，将 HDAC 抑制剂与抗微管蛋白药物（例如 紫杉醇）将增强治疗耐药和/或复发性 PDAC 患者的疗效。