Epigenetic mechanisms of therapeutic resistance

治疗耐药的表观遗传机制

• 批准号: 10434103
• 负责人: KORNELIA POLYAK
• 金额: $ 35.88万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434103
• 关键词: ATAC-seq; Affect; Bar Codes; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Bromodomain; CRISPR screen; CRISPR/Cas technology; Cell Count; Cells; ChIP-seq; Chemoresistance; Combined Modality Therapy; Data; Development; Disease Progression; Disease-Free Survival; Drug Tolerance; Endocrine; Enzymes; Epigenetic Process; Estrogen Antagonists; Estrogen receptor positive; Evolution; Frequencies; Genetic; Genomics; Goals; Heterogeneity; Histone H3; Histones; Human; In Vitro; Individual; KDM5B gene; Knowledge; Lysine; MCF7 cell; Mammary Neoplasms; Molecular; Oncogenes; Paclitaxel; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Population; Population Decreases; Population Dynamics; Prognosis; Publishing; Regulation; Reporting; Research; Resistance; Role; Route; Signal Transduction; Specificity; Testing; Therapeutic; Therapeutic Agents; Time; Validation; Variant; acquired treatment resistance; anti-cancer therapeutic; base; cancer cell; cancer therapy; chemotherapy; design; effective therapy; epigenetic drug; epigenetic therapy; epigenomics; experimental study; genome-wide; hormone therapy; improved; in vivo; inhibitor; malignant breast neoplasm; mathematical model; neoplastic; novel therapeutics; overexpression; resistance mechanism; response; single-cell RNA sequencing; small molecule; therapeutic target; therapy resistant; transcriptome; transcriptomics; treatment response; treatment strategy; triple-negative invasive breast carcinoma; tumor

Project Summary/Abstract Cellular phenotypic heterogeneity is a key mechanism underlying neoplastic disease progression and therapeutic resistance, yet its regulation is poorly understood at the molecular level. We have found that elevated therapeutic resistance is associated with higher levels of cell-to-cell transcriptomic heterogeneity and that decreasing such heterogeneity by modulating the activity of epigenetic histone-modifying enzymes such as KDM5B improves responses to treatment. We also determined that acquired resistance to epigenetic drug agents, including KDM5 and BET bromodomain inhibitors, is due to epigenetic mechanisms, whereas acquired endocrine resistance reflects a selection for a pre-existing, genetically distinct sub-populations of cells. The goal of this Project is to investigate the population dynamics of cellular phenotypic heterogeneity in response to and resistance to cancer therapies in luminal estrogen receptor positive (ER+) and triple-negative breast cancer (TNBC). Our hypothesis is that cellular states governed by epigenetic regulators are highly variable and dynamic and that this underlies acquired therapeutic resistance. We also hypothesize that by modulating the activity of epigenetic regulators and by identifying mechanisms of synthetic lethality and the acquired resistance to epigenetic agents, we can decrease transcriptomic heterogeneity and improve therapeutic response. To test our hypotheses, we will characterize the impact of genetic and epigenetic heterogeneity on acquired resistance to endocrine, chemo-, and epigenetic therapies (Aim 1). We will use barcoded cells to follow population dynamics during the development of acquired resistance, characterize the epigenetic landscape and transcriptomic heterogeneity of drug-tolerant and -resistant populations, and build mathematical models based on experimental data to predict the evolution of therapeutic resistance to different agents. Additionally, to define synthetic-lethal interactions and mechanism of acquired resistance to epigenetic therapies we will perform CRISPR/Cas9 screens (Aim 2) in ER+ and TNBC cell lines that are sensitive versus resistant to epigenetic agents. Overall, the project will significantly advance our knowledge of the regulation of phenotypic heterogeneity and the role this plays in therapeutic responses and resistance.

项目概要/摘要 细胞表型异质性是肿瘤疾病进展的关键机制 治疗耐药性，但其在分子水平上的调节却知之甚少。我们发现，升高 治疗耐药性与较高水平的细胞间转录组异质性相关，并且 通过调节表观遗传组蛋白修饰酶的活性来减少这种异质性，例如 KDM5B 改善治疗反应。我们还确定了对表观遗传药物的获得性耐药性 药物，包括 KDM5 和 BET 溴结构域抑制剂，是由于表观遗传机制引起的，而获得性的 内分泌抵抗反映了对预先存在的、遗传上不同的细胞亚群的选择。目标 该项目的目的是研究细胞表型异质性的群体动态响应和 管腔雌激素受体阳性 (ER+) 和三阴性乳腺癌对癌症治疗的耐药性 （TNBC）。我们的假设是，由表观遗传调节因子控制的细胞状态是高度可变和动态的 这就是获得性治疗耐药性的基础。我们还假设通过调节 表观遗传调节剂并通过识别合成致死机制和获得性抗性 表观遗传剂，我们可以减少转录组异质性并改善治疗反应。来测试我们的 假设，我们将描述遗传和表观遗传异质性对获得性耐药性的影响 内分泌、化疗和表观遗传疗法（目标 1）。我们将使用条形码细胞来跟踪种群动态 在获得性抗性的发展过程中，描述表观遗传景观和转录组学特征 耐药人群的异质性，并根据实验建立数学模型 预测对不同药物的治疗耐药性演变的数据。此外，定义合成致死 表观遗传疗法获得性耐药的相互作用和机制我们将进行 CRISPR/Cas9 在 ER+ 和 TNBC 细胞系中筛选（目标 2）对表观遗传因子敏感和耐药的细胞系。总体而言， 该项目将显着提高我们对表型异质性调控及其作用的认识 在治疗反应和抵抗中发挥作用。