Project 4: Chromatin Remodeling Drives the Adaptive Resistance Response to Targeted Kinase Inhibition in Breast Cancer

项目 4：染色质重塑驱动乳腺癌对靶向激酶抑制的适应性耐药反应

基本信息

批准号：
10468787
负责人：
GARY L. JOHNSON
金额：
$ 33.8万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-08-05 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468787
关键词：
Automobile Driving BRAF gene Biopsy Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Bromodomain Bypass Cell model Cells Characteristics Chemotherapy-Oncologic Procedure Clinical Clinical Treatment Clinical Trials Combined Modality Therapy Complex Coupled DDR1 gene Data Development Disease Disease Resistance Drug resistance EGFR inhibition ERBB2 gene Enhancers Epigenetic Process Exhibits Failure Future Gene Expression Generations Genetic Transcription Genetically Engineered Mouse Genome Genomics Growth Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Human Human Biology Industry KRAS2 gene Letters Lysine MAP Kinase Gene MEK inhibition MEKs Mass Spectrum Analysis Methods Minority Mutation Oncogenic PTEN gene Pathway interactions Patient-derived xenograft models of breast cancer Patients Pharmaceutical Preparations Phase Phase I/II Trial Phenotype Phosphotransferases Plant Roots Positive Transcriptional Elongation Factor B Pre-Clinical Model Process Protein Acetylation Protein Tyrosine Kinase Proteomics Proto-Oncogene Proteins c-akt RNA Receptor Activation Receptor Protein-Tyrosine Kinases Recurrent disease Resistance Resistance development Safety Signal Transduction Site TP53 gene Testing Therapeutic Time Transcriptional Activation Up-Regulation cancer therapy chemotherapy chromatin remodeling early phase clinical trial efficacy testing epigenomics genome-wide inhibitor kinase inhibitor lapatinib malignant breast neoplasm neoplastic cell patient response pre-clinical prevent promoter receptor recruit resilience resistance mechanism response targeted agent targeted treatment therapeutic target therapy resistant transcriptome sequencing transcriptomics triple-negative invasive breast carcinoma tumor tumor growth

项目摘要

Project 4 Abstract Triple Negative Breast Cancer (TNBC), which includes Claudin-low (CL) and Basal-like Breast Cancer (BL), exhibits frequent TP53 mutation and large-scale copy number changes. Genomic changes also result in nearly 80% of BL having MEK/ERK pathway activation, yet targeted agents have not been effective in TNBC, and chemotherapy remains the option for recurrent disease. We have shown in TNBC that targeting signaling nodes crucial for tumor growth, such as MEK/ERK, elicits rapid upregulation of alternative kinase networks contributing to escape from growth inhibition. This adaptive kinome remodeling is distinct from the time- dependent selection of pathway mutations/amplifications that constitute a well-studied resistance mechanism in multiple tumor types. Pharma is beginning to overcome some of these mutations with 2nd and 3rd generation agents, but we don’t have answers for adaptive reprogramming. Our data show that adaptive reprogramming after trametinib (MEK inhibitor) and entinostat (HDAC inhibitor) in TNBC and laptinib in HER2+ disease result in slightly different, but widespread, transcriptional upregulation of multiple kinases making combination therapy with multiple kinase inhibitors impractical and potentially toxic. The mechanism underlying the transcriptomic changes are driven epigenetically with de novo enhancer formation and dramatic genome-wide enhancer and promoter remodeling. Enhancer remodeling is not restricted to MEK inhibition; we have observed adaptive reprogramming in response to inhibitors for AKT, PI3K, HDACs (entinostat) and receptor tyrosine kinases. Importantly, using a 7-day trametinib window trial in TNBC patients we demonstrated that adaptive kinome reprogramming is recapitulated in patients. Lastly our recent data show that bromodomaim inhibitors can both prevent and reverse the epigenetic changes working as the root cause of adaptive reprogramming. Our objective is to, for the first time in patients with TNBC, establish the occurrence of rapid epigenetic reprogramming thereby developing the rationale for combination trials of clinically advancing BRD4 inhibitors with either trametinib or entinostat. This could restore targeted therapies to TNBC treatment. Aim 1: Determine MEKi (trametinib) and HDACi (entinostat) induced alterations in enhancer function, chromatin remodeling, and gene expression driving adaptive bypass resistance in TNBC PDXs, PDX-derived primary cells and GEM models by analyzing genomic, epigenomic and protein acetylation. Aim 2. Use BRD4 inhibitors to determine efficacy in preventing and reversing adaptive resistance to trametinib or entinostat using Aim 1 TNBC models testing the ability of combinations to induce and maintain regression. Aim 3. Use two window trials to obtain pretreatment and 7-day biopsies and analyze selective effects of trametinib vs entinostat on enhancer remodeling and transcriptional changes in TNBC patient tumors comparing the patient response to primary cells from the same tumor. The results would form the basis for future Phase 1/2 trials using trametinib or entinostat combinations with clinically advancing BRD4 inhibitors.

项目4摘要三阴性乳腺癌（TNBC），包括低克劳丁乳腺癌（CL）和基底样乳腺癌（BL），表现出频繁的 TP53 突变和大规模拷贝数变化也导致了近乎 80% 的 BL 具有 MEK/ERK 通路激活，但靶向药物对 TNBC 无效，并且化疗仍然是治疗复发性疾病的选择。我们在 TNBC 中证明了靶向信号传导。对肿瘤生长至关重要的节点，例如 MEK/ERK，引发替代激酶网络的快速上调这种适应性激酶组重塑与时间抑制不同。路径突变/扩增的依赖性选择构成了经过充分研究的耐药机制在多种肿瘤类型中，制药公司开始通过第二代和第三代克服其中一些突变。代理，但我们没有适应性重编程的答案。我们的数据表明适应性重编程。在 TNBC 中使用曲美替尼（MEK 抑制剂）和恩替司他（HDAC 抑制剂）以及在 HER2+ 疾病中使用拉普替尼后结果多种激酶的转录上调略有不同，但广泛存在，从而形成组合使用多种激酶抑制剂进行治疗不切实际且具有潜在毒性。转录组变化是通过表观遗传学从头增强子形成和显着的全基因组驱动的增强子和启动子重塑不限于MEK抑制；观察到响应 AKT、PI3K、HDAC（entinostat）和受体抑制剂的适应性重编程重要的是，我们在 TNBC 患者中进行了 7 天曲美替尼窗口试验，证明了这一点。我们最近的数据显示，适应性激酶组重编程最终在患者身上得到了体现。抑制剂可以预防和逆转表观遗传变化，这是适应的根本原因我们的目标是首次在 TNBC 患者中确定快速发生的情况。表观遗传重编程从而为临床进展的 BRD4 联合试验提供了理论依据曲美替尼 (Trametinib) 或恩替司他 (entinostat) 抑制剂这可以恢复 TNBC 治疗的靶向治疗。目标 1：确定 MEKi（曲美替尼）和 HDACi（恩替司他）诱导的增强子功能改变，染色质重塑和基因表达驱动 TNBC PDX、PDX 衍生的适应性旁路耐药性通过分析基因组、表观基因组和蛋白质乙酰化来建立原代细胞和 GEM 模型。目标 2. 使用 BRD4 抑制剂确定预防和逆转曲美替尼适应性耐药的功效或恩替司他使用 Aim 1 TNBC 模型测试组合诱导和维持回归的能力。目标 3. 使用两个窗口试验获得预处理和 7 天活检并分析曲美替尼与恩替司他对 TNBC 患者肿瘤增强子重塑和转录变化的影响比较患者对来自同一肿瘤的原代细胞的反应，结果将构成以下研究的基础。未来的 1/2 期试验将使用曲美替尼或恩替司他与临床先进的 BRD4 抑制剂组合。