Mechanism of estrogen independent proliferation in ER+ breast cancer cells

ER乳腺癌细胞雌激素非依赖性增殖机制

基本信息

批准号：
10737869
负责人：
Aritro Nath
金额：
$ 9.15万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737869
关键词：
Acceleration Automobile Driving Biological Models Biopsy Breast Cancer Cell Breast Cancer Patient Bypass CDK4 gene Cancer Control Cancer Patient Cell Cycle Cell Cycle Checkpoint Cell Cycle Progression Cell Cycle Regulation Cell Line Cell Lineage Cell Proliferation Cell division Cells Cessation of life Chemosensitization Clinical Clinical Trials Collection Combined Modality Therapy Couples Cyclin-Dependent Kinase Inhibitor Data Dose Drug Combinations Drug Modelings Drug usage ERBB2 gene Effectiveness Endocrine Equilibrium ErbB4 gene Estrogen receptor positive Estrogens Evolution Feedback Gene Expression Gene Expression Profile Hand In Vitro Letrozole MAP Kinase Gene Maps Measurement Measures Mediating Mitogen-Activated Protein Kinase Kinases Modeling Outcome Study Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phosphotransferases Population Preoperative Endocrine Therapy Proliferating Repression Resistance Role Sampling Series Signal Pathway Signal Transduction System Testing Therapeutic Time Tumor stage Up-Regulation cancer cell cell type design drug testing experimental study hormone therapy improved outcome in vitro Model in vivo inhibitor kinase inhibitor malignant breast neoplasm mathematical model neoplastic cell patient response personalized medicine prevent promoter reconstruction refractory cancer resistance mechanism response single-cell RNA sequencing targeted treatment therapy resistant tool transcriptomics treatment strategy tumor tumor heterogeneity

项目摘要

Abstract Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic estrogen receptor positive (ER+), HER2 negative, breast cancer patients. However, the value of this combination in potentially curable earlier stage patients is variable. Our preliminary results examined the evolutionary trajectories of early stage breast cancer tumors using single cell transcriptomic profiling of serial tumor biopsies from a clinical trial of preoperative endocrine therapy alone (letrozole) or in combination with the cell cycle inhibitor ribociclib. Resistant tumors with accelerated loss of estrogen signaling show up-regulation of the JNK pathway, while those that maintain estrogen signaling during therapy show potentiation of CDK4/6 activation consistent with ERBB4 and ERK signaling up-regulation. Cell cycle reconstruction identified that tumors cells can reactivate during combination treatment, indicating stronger selection for a proliferative state. We hypothesize that resistance to CDK4/6 inhibition in earlier stage breast cancer is driven by JNK MAPK pathway stimulation and reactivation of the cell cycle through promotion of CDK6 expression or decreased cell cycle inhibitor function. In Aim 1, we will use a new mechanistic model of CDK4/6 regulation by cell cycle Inhibitors and Promoters (CIP) that couples estrogen and JNK signaling with cell cycle progression to measure the mechanisms driving cell cycle activation in a series of isogenic cell lines sensitive and resistant to CDK4/6 and endocrine inhibitors and in patient tumor cells. This analysis will reveal how distinct signaling pathways contribute to cell cycle reactivation during estrogen, CDK4/6 and JNK inhibition treatments and provide signatures of each resistant mechanism across cell types, over time and between systems. Aim 2 leverages our collection of patient tumors from the FELINE clinical trial to discover the intracellular and intratumoral resistance mechanisms driving proliferation. Fundamental resistance mechanisms will be measured in over ~300,000 patient cells from 360 tumor samples using single cell RNA sequencing data already in hand to identify core intracellular signaling states that act alone or in concert to drive proliferation. Next, the population of cells within each tumor will be analyzed to quantify intratumoral heterogeneity and how resistant populations differ in growing or shrinking tumors during drug treatment. Applying CIP to project proliferation across patient tumor cells will allow prediction of inhibitor strategies that most effectively block intracellular and intratumoral proliferation. Lastly, Aim 3 will apply a series of JNK pathway drugs with clinical potential to design and test treatment strategies that maintain durable inhibition of proliferation in ER+ cancer cells. Iterative feedback between mathematical models and patient/experimental data serves to provide a deep understanding of cell cycle regulation and mechanisms of dysregulation leading to resistance. Together, these experiments will reveal the balance between estrogen and alternative mediated JNK signaling, and their roles in resistance and provide a guide for therapeutic regimes with more durable control of cancer cell proliferation.

抽象的结合细胞周期蛋白依赖性激酶（CDK）抑制剂与内分泌疗法可改善转移的结果雌激素受体阳性（ER+），HER2阴性，乳腺癌患者。但是，这种组合的价值在潜在的可治疗早期阶段中，患者是可变的。我们的初步结果检查了进化使用单细胞转录组的早期乳腺癌肿瘤的轨迹从术前内分泌疗法（LETROZOL）或与细胞周期结合的临床试验抑制剂Ribociclib。雌激素信号传导加速损失的抗性肿瘤显示JNK的上调途径，而治疗过程中维持雌激素信号的途径则显示CDK4/6激活的增强与ERBB4和ERK信号上调一致。细胞周期重建确定肿瘤细胞可以在组合处理过程中重新激活，表明对增生状态的选择更强。我们假设在早期乳腺癌中对CDK4/6抑制的抵抗力是由JNK MAPK驱动的通过促进CDK6表达或细胞周期抑制剂功能降低。在AIM 1中，我们将使用CDK4/6法规的新机械模型通过细胞周期抑制剂和启动子（CIP），将雌激素和JNK信号与细胞周期进程伴测量在一系列等生细胞系敏感和抗性的一系列驱动细胞周期激活的机制到CDK4/6和内分泌抑制剂和患者肿瘤细胞中。该分析将揭示如何不同的信号途径有助于雌激素，CDK4/6和JNK抑制作用期间的细胞周期重新激活，并提供随着时间的推移和系统之间的跨类型跨类型的每个抗性机制的签名。目标2利用我们的从猫科动物临床试验中收集患者肿瘤，以发现细胞内和肿瘤内耐药性驱动增殖的机制。基本阻力机制将在〜30万以上测量使用单细胞RNA测序数据来自360个肿瘤样品的患者细胞已经识别核心细胞内信号传导单独起作用或共同行动以驱动增殖。接下来，内部的细胞种群每个肿瘤将进行分析以量化肿瘤内异质性，以及耐药种群在增长方面的差异或在药物治疗期间收缩肿瘤。将CIP应用于跨患者肿瘤细胞的增殖，将允许预测最有效地阻止细胞内和肿瘤内增殖的抑制剂策略。最后， AIM 3将应用一系列具有临床潜力的JNK途径药物来设计和测试治疗策略维持ER+癌细胞增殖的持久抑制作用。数学模型之间的迭代反馈患者/实验数据可深入了解细胞周期调节和机制失调导致抗性。这些实验将共同揭示雌激素之间的平衡和替代介导的JNK信号及其在电阻中的作用，并为治疗方案提供指南更耐用的癌细胞增殖。