Chromatin remodeling and FOXO in targeting CDK4 in mantle cell lymphoma

染色质重塑和 FOXO 在套细胞淋巴瘤中靶向 CDK4

• 批准号: 9524114
• 负责人: SELINA Y CHEN-KIANG
• 金额: $ 38.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-02 至 2018-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9524114
• 关键词: Address; Agammaglobulinaemia tyrosine kinase; Attenuated; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Biological Assay; Bortezomib; CDK4 gene; Cause of Death; Cell Cycle; Cell Cycle Regulation; Cell Death; Cell Line; Cell Nucleus; Cells; Chromatin; Chromosomal translocation; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Cyclin D1; Cyclin-Dependent Kinase Inhibitor 2A; Development; Disease; Disease Progression; Drug resistance; EZH2 gene; Enhancers; Epigenetic Process; Event; FOXO1A gene; G1 Arrest; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Goals; Homeostasis; Human; In Vitro; Light; Lymphoma; Malignant Neoplasms; Mantle Cell Lymphoma; Mediating; Metabolism; Modeling; Mutation; Oxidation-Reduction; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Polycomb; Receptors, Antigen, B-Cell; Recurrence; Regulation; Resistance; Role; Signal Transduction; Stress; Testing; Time; Transposase; Tumor Suppressor Proteins; base; cancer cell; cancer therapy; chromatin remodeling; clinical efficacy; cytotoxic; drug development; exome sequencing; gain of function; histone methyltransferase; improved; in vivo; inhibitor/antagonist; loss of function; neoplastic cell; novel; prevent; promoter; response; targeted agent; transcription factor; transcriptome; transcriptome sequencing; tumor

Mantle cell lymphoma (MCL) is a B cell non-Hodgkin lymphoma (NHL) that remains largely incurable due to development of drug resistance. Disease progression in MCL is invariably associated with unrestrained proliferation of tumor cells caused by dysregulated CDK4 activity and aberrant cyclin D1 expression. Targeting CDK4, therefore, is a rational approach to MCL therapy. The first phase I clinical trial targeting CDK4 with PD 0332991 (palbociclib, the first selective CDK4/6 inhibitor) in recurrent MCL resulted in durable clinical responses with tumor regression in some MCL patients. Inhibition of CDK4, therefore, not only prevents proliferation of cancer cells but also enhances their vulnerability. Ongoing clinical trials combining palbociclib with bortezomib or with ibrutinib, which inhibits BTK required for MCL survival, support the clinical efficacy of targeting CDK4. Longitudinal integrative analysis of whole transcriptome–sequencing and whole exom- sequencing further reveals that inhibition of CDK4 leads to prolonged early G1 arrest (pG1) in all patients but clinical response is associated with differential regulation of genes that are involved in PI3K inactivation, metabolism and redox stress. To address the underlying mechanism, we discovered that pG1 induced repressive chromatin remodeling by differential regulation of EZH1 and EZH2, histone methyltransferases for H3K27me2/3, in responding patients, and timely inhibition of EZH1/EZH2 led to synergistic killing of MCL cells in pG1. These results suggest that chromatin remodeling is a critical proximal event in pG1 reprogramming. Moreover, pG1 sensitizes MCL cells to killing by ibrutinib and by inhibition of PI3K, and this requires the action of the FOXO1 transcription factor, which is activated and localized to the nucleus in pG1. FOXO1 is a central component of the PI3K signaling and also acts as a tumor suppressor in a context-dependent manner. Based on our novel preliminary findings, we hypothesize that induction of pG1 by CDK4 inhibition causes specific epigenetic alterations that modify FOXO1's access to its target genes, which in turn alters the expression of FOXO1-dependent cytotoxic genes for clinical response to targeting CDK4 in MCL. Our goal is to advance hypothesis-driven, effective and durable cell cycle therapy in cancer by defining the mechanisms of cell cycle reprogramming. To achieve this goal, we will test our hypothesis in two Specific Aims: 1) To elucidate the role of EZH1 and EZH2 in chromatin remodeling in pG1 reprogramming by elucidate chromatin remodeling in pG1 transcriptional reprogramming and determining the functional consequence of cell cycle regulation of EZH1/EZH2; and 2) To define the role of FOXO1 in CDK4 inhibitor sensitization to BTK or PI3K inhibition by determine the significance of cell cycle regulation of FOXO1 and identifying the transcriptional targets of FOXO1 that mediates pG1 sensitization to clinical response. Successful completion of the proposed studies should shed light on the mechanism of cell cycle control of chromatin remodeling and FOXO activation, which has important and broad clinical implications.

地幔细胞淋巴瘤（MCL）是B细胞非霍奇金淋巴瘤（NHL），由于 耐药性的发展。 MCL的疾病进展总是与不受约束的 由CDK4活性失调和异常细胞周期蛋白D1表达引起的肿瘤细胞的增殖。定位 因此，CDK4是MCL治疗的合理方法。用PD靶向CDK4的第一阶段I临床试验 0332991（Palbociclib，第一个选择性CDK4/6抑制剂）在复发MCL中产生持久的临床 一些MCL患者的肿瘤消退反应。因此，抑制CDK4不仅可以防止 癌细胞的增殖，但也增强了其脆弱性。正在进行的临床试验结合了palbociclib 使用硼替佐米或ibrutinib抑制MCL生存所需的BTK，支持临床效率 靶向CDK4。纵向综合分析整个转录组 - 序列和整个外部的综合分析 测序进一步表明，抑制CDK4会导致所有患者的延长G1停滞（PG1），但 临床反应与涉及PI3K失活的基因的不同调节有关， 代谢和氧化还原应激。为了解决潜在机制，我们发现PG1诱导了 通过EZH1和EZH2的差分调节，Hisstone甲基转移酶的抑制性染色质重塑 H3K27ME2/3，在反应患者中，及时抑制EZH1/EZH2导致MCL细胞的协同杀伤 在PG1中。这些结果表明，染色质重塑是PG1重编程中的关键代理事件。 此外，PG1感知MCL细胞被ibrutinib杀死并抑制PI3K，这需要采取行动 FOXO1转录因子，该因子被激活并定位于Pg1中的核。 FOXO1是中央 PI3K信号的成分以及以上下文依赖性方式充当肿瘤抑制器。基于 在我们新的初步发现中，我们假设CDK4抑制对PG1的诱导会导致特定 表观遗传学改变改变了FOXO1对其靶基因的访问，从而改变了表达 FOXO1依赖性细胞毒性基因，用于靶向MCL中靶向CDK4的临床反应。我们的目标是进步 通过定义细胞周期的机制，假设驱动，有效且耐用的细胞周期治疗 重新编程。为了实现这一目标，我们将以两个具体目的测试我们的假设：1）阐明 EZH1和EZH2在染色质重塑中的作用在PG1重塑中通过阐明染色质重编程 PG1转录重编程和确定细胞周期功能后果的重塑 EZH1/EZH2的调节; 2）定义FOXO1在CDK4抑制剂对BTK或BTK或 通过确定FOXO1的细胞周期调节的重要性并鉴定PI3K抑制 FOXO1的转录靶标介导PG1对临床反应的敏感性。成功完成 在拟议的研究中，应阐明染色质重塑和 Foxo激活，具有重要且广泛的临床意义。