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: 10686309
• 负责人: Monique B Nilsson
• 金额: $ 10.14万
• 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/10686309
• 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; mutant; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; prevent; resistance mechanism; treatment strategy; tumor; tumor eradication

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 识别可靶向驱动器的癌基因（例如EGFR）是革命性的 促进肺癌和其他恶性肿瘤的治疗。在具有这种遗传的肿瘤中 驱动器，绝大多数细胞取决于特定的癌基因生存（通常 有效的抑制剂可以急剧 改善患者的临床结果，但大多数时候这些药物并非完全 根除肿瘤，留下未被初始治疗杀死的残留细胞。这些细胞， 称为耐药的持久性持久性细胞（DTPC），可能保持静止或临床看不见 长时间的时间，有时会发展成为抗性细胞，并增强 转移潜力。过去十年来我的实验室研究工作一直集中在 很大一部分，阐明对EGFR酪氨酸激酶抑制剂（TKI）和 制定克服抵抗的策略，已转化为新药的努力 并组合进入诊所（例如，poziotinib，Axl+EGFR抑制剂，VEGF+EGFR抑制剂， ETC）。莫妮克·尼尔森（Monique Nilsson）博士一直在领导其中一些研究，包括鉴定 应力激素和IL-6作为EGFR TKI抗性的驱动力和表征 YAP/FOXM1轴是EGFR TKI电阻发展的关键途径。她也是 确定了EGFR突变体TKI耐药性肿瘤（如Aurora激酶）的新靶标。更多的 最近，她能够在vegf前链式链式链接演示 EGFR突变肺肿瘤的依赖性。重要的是，尼尔森博士的研究导致了一些新的 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博士在此提案中的目标是确定新颖的 在早期消除DTPC的治疗策略。关于 DTPC的信号通路和潜在的治疗漏洞，我们旨在执行 在我的实验室的大量临床前模型的单细胞水平上进行深入分析 尼尔森博士在过去几年中已经发展。我们相信这些研究也将 帮助您了解其他分子定义的致癌基因驱动的肺亚型 和其他实体瘤。