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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：
10304408
负责人：
ANDREA Hope BILD
金额：
$ 59.62万
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/10304408
关键词：
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 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 Repression Resistance Role Sampling Series Signal Pathway Signal Transduction System Testing Therapeutic Time Transitional Cell Neoplasm Tumor stage Up-Regulation base cancer cell cell type design drug testing experimental study hormone therapy improved outcome in vitro Model in vivo inhibitor/antagonist 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.

摘要