Epigenetic mechanisms of gemcitabine resistance in pancreatic cancer

胰腺癌吉西他滨耐药的表观遗传机制

• 批准号: 10316214
• 负责人: Chan D Nguyen
• 金额: $ 3.41万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-10 至 2022-12-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316214
• 关键词: Affect; Affinity; Arginine; Binding; CRISPR/Cas technology; Cells; Chemoresistance; Chromatin; Combination Drug Therapy; Combined Modality Therapy; Complex; Cytostatics; DNA; DNA Methylation; Development; Disease; Disease Progression; Epigenetic Process; Genetic; Genetic Transcription; Genomic approach; Genomics; Human; Immunocompetent; In Vitro; Knock-out; Knowledge; Lead; Lysine; MLL gene; Malignant neoplasm of pancreas; Mediating; Menin; Methylation; Methyltransferase; Modeling; Mus; Neoplasms; Pancreatic Ductal Adenocarcinoma; Pharmaceutical Preparations; Phase; Phase Transition; Resistance; Resistance development; Role; Survival Rate; Tissue-Specific Gene Expression; Validation; arginine methyltransferase; base; chemotherapy; epigenomics; functional genomics; gemcitabine; histone modification; in vivo; inhibitor; insight; knock-down; mutant; novel; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; reconstitution; response; small hairpin RNA; small molecule; transcriptome sequencing; transcriptomics; tumor

Project Summary Pancreatic ductal adenocarcinoma (PDAC) is the fourth most lethal neoplasm in the US with 5- year-survival rate of 8.5%. Currently, gemcitabine single agent or combination chemotherapies remain the most commonly used frontline treatment for locally invasive and metastatic PDAC. However, most PDAC tumors are intrinsically resistant or quickly acquire resistance to gemcitabine. Epigenetic reprogramming through changes in global DNA methylation or histone modification have been implicated in chemoresistance. Here, I established a model for gemcitabine resistance progression in PDAC and identified a cytostatic transition phase prior to regrowth under gemcitabine treatment. Through a small-molecule epigenetic inhibitor screen, I identified PRMT1 (H4R3 arginine methyltransferase) and KMT2A/B (H3K4 lysine methyltransferase) as positive and negative regulators of transition into gemcitabine resistance, respectively. Based on these findings, I hypothesize that PDAC cells transition into gemcitabine resistance through epigenetic reprogramming that is in part mediated by PRMT1 and KMT2A/B. In Aim 1, I will functionally validate PRMT1 and KMT2A/B in modulating PC gemcitabine resistance in vitro and in vivo. In Aim 2, I will investigate the mechanisms by which PRMT1 and KMT2A/B modulate gemcitabine resistance through integrated genomic analysis. Collectively, I expect my study will shed important new insight into the mechanisms of gemcitabine resistance in PDAC, which could lead to novel combination therapies to enhance the efficacies and durability of gemcitabine in PDAC.

项目摘要 胰腺导管腺癌(PDAC)是美国第四大致命性肿瘤，占 1年存活率为8.5%。目前，吉西他滨单药或联合化疗 仍然是局部侵袭性和转移性PDAC最常用的一线治疗方法。 然而，大多数PDAC肿瘤是天生耐药的，或者很快就对 吉西他滨。通过全球DNA甲基化或组蛋白的变化进行表观遗传重编程 基因修饰被认为与化疗耐药有关。在这里，我为 吉西他滨在PDAC中的耐药进展和在此之前发现的细胞抑制过渡期 在吉西他滨治疗下再生长。通过小分子表观遗传抑制物筛选，我 鉴定了PRMT1(H4R3精氨酸甲基转移酶)和KMT2A/B(H3K4赖氨酸 甲基转移酶)作为转化为吉西他滨耐药的正负调节因子， 分别进行了分析。基于这些发现，我假设PDAC细胞转化为吉西他滨 部分由PRMT1和KMT2A/B介导的表观遗传重编程产生的抗性。 在目标1中，我将从功能上验证PRMT1和KMT2A/B在调节PC吉西他滨中的作用 体外和体内耐药。在目标2中，我将研究PRMT1和PRMT1 通过整合基因组分析，KMT2A/B调控吉西他滨的耐药性。总而言之，我 期待我的研究将为吉西他滨耐药机制提供重要的新见解 在PDAC中，这可能导致新的联合疗法来增强有效性和耐受性 吉西他滨在PDAC中的应用。