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：
10329992
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/10329992
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 Progression 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 Knowledge Laboratories Lesion Lung Neoplasms MAP Kinase Gene Malignant neoplasm of lung Mitotic Mitotic Activity Modeling Molecular Molecular Genetics Mutate Mutation Non-Small-Cell Lung Carcinoma Oncogenes Oncology Organoids Other Genetics Patients Pharmaceutical Preparations Pharmacotherapy Phase Phosphotransferases Play Process Proteomics Residual Tumors Resistance Role Sampling Seminal Sequential Treatment Shapes Signal Transduction Source Stress Systems Biology Testing Therapeutic 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 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耐药性是肿瘤学和提高患者生存率的主要挑战。作为一个典型的例子是，EGFR 酪氨酸激酶抑制剂 (TKI) 对许多 EGFR 突变的非小细胞肺癌患者。然而，这些患者在获得有希望的初步反应后总是会出现获得性耐药性的发展，通常是致命的事件。其细胞基础源于不完全的初始反应形成由肿瘤细胞持久性和药物引起的残留疾病库通过知之甚少的机制来实现宽容。在大量的初步数据中，我们发现 EGFR 突变肺癌细胞的持久性和耐药性取决于有丝分裂应激反应由药物治疗引起。耐药肿瘤细胞依赖于持续的有丝分裂应激信号传导，并且在体外和体内都容易受到极光激酶抑制剂的影响。来自进展患者的肿瘤样本 EGFR 抑制剂经常表现出持续应激信号传导的证据，通常与其他抑制剂同时发生遗传变化通常与耐药性相关。在这里，我们试图机械地剖析这是如何应激信号有助于肿瘤细胞的持久性和获得性抵抗及其在肿瘤形成中的作用治疗后的进化。我们将检验以下假设：急性致癌基因戒断所产生的压力会导致 EGFR TKI 治疗期间无法解释的耐药性和残留疾病的关键特征是：细胞适应和对细胞凋亡的抵抗（目标 1）以及导致 de 的遗传进化的催化新获得的耐药性导致突变（目标 2）。最后，这些知识将用于识别新的通过限制应激信号传导来阻止肿瘤进化的治疗策略（目标 3）。为了解决这个问题假设，我们的团队由肺癌、系统生物学和临床转化方面的专家组成，并将使用创新的新单细胞方法、活细胞成像、最先进的动物和类器官模型以及患者样本。我们的目标是奠定机制基础，改变当前的范式出现抵抗后，针对获得性抵抗的反应性方法转变为针对目标的主动方法残留疾病的来源，以防止获得性耐药性。