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

• 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
• 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

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.

摘要 对靶向治疗的耐药性是肿瘤学的主要挑战，也是提高患者生存率的障碍。作为 典型的定义性实例，EGFR酪氨酸激酶抑制剂（TKI）在许多EGFR突变的非肿瘤细胞中是有效的。 小细胞肺癌患者。然而，在这些患者中，有希望的初始反应总是伴随着 获得性抗性的发展，通常是致命的。这一现象的细胞基础来自于 不完全的初始反应，形成由肿瘤细胞持续存在和药物引起的残留疾病库 通过不太了解的机制。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药物耐受性依赖于有丝分裂应激反应 由药物治疗引起的。药物耐受性肿瘤细胞依赖于持续的有丝分裂应激信号传导， 在体外和体内易受极光激酶抑制剂的影响。进展患者的肿瘤样本 EGFR抑制剂经常显示持续应激信号传导的证据，通常与其他药物同时发生。 通常与耐药性相关的遗传变化。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抗性， 治疗后的进化我们将检验这样一个假设，即急性癌基因戒断引起的压力驱动了 EGFR TKI治疗期间无法解释的药物耐受性和残留疾病的关键特征，即： 细胞适应和抗凋亡（目标1）和遗传进化的催化作用，导致死亡 新获得的耐药性引起突变（目的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演变的治疗策略（Aim 3）。为了解决这个 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，最先进的动物和类器官模型， 患者样本。我们的目标是打好机械基础， 在获得性耐药性出现后，采取针对获得性耐药性的被动方法， 残留病源，防止获得性耐药。