Targeting EGFR mutant tyrosine kinase inhibitors (TKIs) resistant and drug-tolerant persister cells in non-small cell lung cancer (NSCLC)

靶向非小细胞肺癌 (NSCLC) 中 EGFR 突变型酪氨酸激酶抑制剂 (TKI) 耐药和耐药持久细胞

• 批准号: 10322233
• 负责人: Monique B Nilsson
• 金额: $ 14.03万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322233
• 关键词: Cells; Clinic; Clinical; Clinical Trials; Collection; Critical Pathways; Dependence; Development; Disease Resistance; Drug Targeting; Drug Tolerance; Drug resistance; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; FOXM1 gene; Genetic; Goals; Growth; Hormones; Institution; Interleukin-6; Laboratories; Laboratory Research; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Molecular; Non-Small-Cell Lung Carcinoma; Oncogenes; Patient-Focused Outcomes; Pharmaceutical Preparations; Pre-Clinical Model; Residual state; Resistance; Signal Pathway; Solid Neoplasm; Stress; Therapeutic; Time; Translating; Tyrosine Kinase Inhibitor; Vascular Endothelial Growth Factors; aurora kinase; improved; inhibitor/antagonist; mutant; novel; novel drug combination; novel therapeutic intervention; pre-clinical; prevent; resistance mechanism; treatment strategy; tumor

Project Abstract/Summary The identification of targetable driver oncogenes, such as EGFR, has been a revolutionary advance in the treatment of lung cancer and other malignancies. In tumors with such genetic drivers, the vast majority of cells are dependent on specific oncogenes for survival (commonly referred to as oncogene “addicted” or oncogene-dependent). Effective inhibitors can dramatically improve clinical outcomes for patients but most of the times these drugs do not completely eradicate tumors leaving residual cells that are not killed by the initial treatment. These cells, termed drug-tolerant persister cells (DTPCs), may remain quiescent or clinically invisible for prolonged periods of time and eventually progress to become resistant cells with enhanced metastatic potential. My laboratory research efforts over the past decade have been focused, in large part, on elucidating mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) and developing strategies to overcome resistance, efforts that have been translated into new drugs and combinations into the clinic (e.g. poziotinib, Axl+EGFR inhibitors, VEGF+EGFR inhibitors, etc). Dr. Monique Nilsson has been leading some of these studies including the identification of stress hormones and IL-6 as drivers of EGFR TKI resistance and the characterization of the YAP/FOXM1 axis as a critical pathway in the development of EGFR TKI resistance. She also identified novel targets for EGFR mutant TKI resistant tumors such as aurora kinases. More recently she was able to demonstrate pre-clinically the mechanisms underlying the VEGF dependency of EGFR mutant lung tumors. Importantly, Dr. Nilsson’s studies led to several new clinical trials that are currently ongoing in our institution. In order to prevent the emergence of drug resistance of EGFR mutant tumors, Dr. Nilsson’s goal in this proposal is to identify novel treatment strategies to eliminate DTPCs in the early stages. There is little known about the signaling pathways and potential therapeutic vulnerabilities of DTPCs and we aimed to perform a deep analysis at the single cell level of a large collection of preclinical models that my laboratory and Dr. Nilsson have developed during the past years. We believe that these studies will also help to advance in the understanding of other molecularly defined oncogene-driven lung subtypes and other solid tumors.

项目摘要/摘要 识别有针对性的致癌基因，如EGFR，是一项革命性的工作 肺癌等恶性肿瘤的治疗进展。在具有这种基因的肿瘤中 驱动因素，绝大多数细胞的生存依赖于特定的癌基因(通常 称为致癌基因“上瘾”或致癌基因依赖)。有效的抑制剂可以戏剧性地 改善患者的临床结果，但大多数情况下，这些药物并不完全 根除肿瘤，留下最初治疗时不会被杀死的残留细胞。这些细胞， 被称为耐药的姊妹细胞(DTPC)，在临床上可能保持静止或不可见 延长了一段时间，最终发展成为具有增强能力的抗性细胞 转移潜能。在过去的十年里，我的实验室研究工作主要集中在 很大程度上是关于阐明对EGFR酪氨酸激酶抑制剂(TKIs)和 制定克服耐药性的战略，已转化为新药的努力 以及进入临床的组合(例如，poziotinib，Axl+EGFR抑制剂，VEGF+EGFR抑制剂， 等)。Monique Nilsson博士一直在领导其中的一些研究，包括识别 应激激素和IL-6作为EGFR TKI耐药的驱动因素及其生物学特性 YAP/FOXM1轴是EGFR TKI耐药的关键途径。她还 确定了EGFR突变的TKI耐药肿瘤的新靶点，如极光激酶。更多 最近，她在临床前证明了血管内皮生长因子的潜在机制。 EGFR突变型肺癌的依赖性。重要的是，尼尔森博士的研究导致了几个新的 我们机构目前正在进行的临床试验。为了防止出现 EGFR突变肿瘤的耐药性，Nilsson博士在这项建议中的目标是识别新的 在早期阶段消除DTPC的治疗策略。人们对此知之甚少 DTPC的信号通路和潜在的治疗脆弱性，我们的目标是进行一项 对我的实验室收集的大量临床前模型进行单细胞水平的深入分析 和尼尔森博士都是在过去几年中发展起来的。我们相信，这些研究也将 有助于促进对其他分子定义的癌基因驱动的肺亚型的理解 和其他实体瘤。