Stress responses drive resistance and shape tumor evolution in EGFR mutant lung cancer

应激反应驱动EGFR突变肺癌的耐药性并塑造肿瘤进化

基本信息

批准号：
10552632
负责人：
Sourav Bandyopadhyay
金额：
$ 49.33万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-20 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552632
关键词：
Acute Address Animals Apoptosis BCL2L11 gene Biological Cancer Biology Cancer Patient Caring Catalysis Cell Line Cell Survival Cells Clinical Trials Complex DNA DNA Sequence Alteration Data Development Disease Reservoirs Drug Tolerance Drug resistance Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Event Evolution Frequencies Generations Genetic Genomic Instability Genotoxic Stress Goals Heterogeneity Hyperactivity In Situ Hybridization In Vitro Induction of Apoptosis Knowledge Laboratories Lesion Lung Neoplasms MAP Kinase Gene Malignant neoplasm of lung Mitotic Mitotic Activity Modeling Molecular Mutate Mutation Non-Small-Cell Lung Carcinoma Oncogenes Oncology Organoids Other Genetics Patients Pharmaceutical Preparations Pharmacotherapy Phase Phosphotransferases Play Process Proteomics Residual Neoplasm Resistance Role Sampling Seminal Sequential Treatment Shapes Signal Transduction Source Stress Systems Biology Testing Therapeutic Tumor Promotion Tumor Stem Cells Tyrosine Kinase Inhibitor Withdrawal acute stress aurora kinase aurora kinase A biological adaptation to stress clinical translation de novo mutation erbB Genes genetic evolution improved in vivo inhibitor innovation insight kinase inhibitor live cell imaging lung cancer cell mouse model mutant neoplastic cell novel novel therapeutic intervention prevent research clinical testing response sensor single cell analysis stem stress kinase targeted treatment treatment strategy trial planning tumor tumor heterogeneity

项目摘要

ABSTRACT Resistance to targeted therapy is a major challenge in oncology and barrier improving patient survival. As a paradigm-defining example, EGFR tyrosine kinase inhibitors (TKIs) are effective in many EGFR-mutated non small-cell lung cancer patients. However, promising initial responses in these patients are always followed by the development of acquired resistance, most often a lethal event. The cellular basis for this stems from an incomplete initial response forming a reservoir of residual disease caused by tumor cell persistence and drug tolerance, through poorly understood mechanisms. In extensive preliminary data we discovered that the persistence and drug tolerance of EGFR-mutant lung cancer cells is dependent on a mitotic stress response elicited by drug treatment. Drug tolerant tumor cells are dependent on continued mitotic stress signaling, and are vulnerable to Aurora Kinase inhibitors in vitro and in vivo. Tumor samples from patients progressing on EGFR inhibitors frequently displayed evidence of ongoing stress signaling, often co-occurring with other genetic changes commonly associated with drug resistance. Here we seek to mechanistically dissect how this stress signaling aids in tumor cell persistence and acquired resistance and the role it plays in shaping tumor evolution after therapy. We will test the hypothesis that stress from acute oncogene withdrawal drives the unexplained and key features of drug tolerance and residual disease during EGFR TKI treatment that is: cellular adaptation and resistance to apoptosis (Aim 1) and the catalysis of genetic evolution leading to the de novo gain of resistance causing mutations (Aim 2). Finally, this knowledge will be used to identify new therapeutic strategies to forestall tumor evolution by limiting stress signaling (Aim 3). To address this hypothesis, our team consists of experts in lung cancer, systems biology and clinical translation and will use innovative new single cell approaches, live cell imaging, state-of-the-art animal and organoid models and patient samples. Our goal is to lay the mechanistic groundwork that shifts the paradigm from the current reactionary approach of targeting acquired resistance after it emerges to a proactive approach that targets sources of residual disease to prevent acquired resistance.

抽象的对靶向治疗的抵抗力是改善患者生存的肿瘤学和障碍的主要挑战。作为定义范式的示例，EGFR酪氨酸激酶抑制剂（TKI）在许多EGFR突出的非非egfr抑制剂中都是有效的小细胞肺癌患者。但是，这些患者的有希望的初始反应总是随后获得的抵抗的发展，通常是致命的事件。此的细胞基础来自肿瘤细胞持久性和药物引起的残留疾病的储层不完全的初始反应宽容，通过知之甚少的机制。在广泛的初步数据中，我们发现 EGFR突变肺癌细胞的持久性和药物耐受性取决于有丝分裂应激反应通过药物治疗引起。药物耐受性肿瘤细胞取决于持续有丝分裂应激信号传导，并且容易在体外和体内受到Aurora激酶抑制剂的影响。来自患者进展的肿瘤样本 EGFR抑制剂经常显示出持续的应力信号传导的证据，通常与其他遗传变化通常与耐药性有关。在这里，我们试图机械地剖析这压力信号有助于肿瘤细胞持久性和获得的抗性及其在塑造肿瘤中所起的作用治疗后的进化。我们将检验以下假设，即急性致癌基因戒断的压力驱动 EGFR TKI治疗期间药物耐受性和残留疾病的无法解释和关键特征是：细胞适应和对凋亡的抗性（AIM 1）以及导致DE的遗传进化的催化 Novo的抗性获得引起突变（AIM 2）。最后，这些知识将用于识别新的知识通过限制压力信号传导来防止肿瘤演变的治疗策略（AIM 3）。解决这个问题假设，我们的团队由肺癌，系统生物学和临床翻译专家组成，将使用创新的新单细胞方法，活细胞成像，最先进的动物和器官模型以及病人样本。我们的目标是为将范式从电流转移的机械基础。靶向获得的抗性的反动方法是在靶向靶向的主动方法之后残留疾病的来源，以防止获得性抗性。