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 靶向驱动癌基因的鉴定，如EGFR，已经是一个革命性的进展。 肺癌和其他恶性肿瘤的治疗进展。在具有这种基因的肿瘤中， 作为驱动因素，绝大多数细胞依赖于特定的癌基因生存（通常 称为癌基因“成瘾”或癌基因依赖性）。有效的抑制剂可以显著地 改善患者的临床结果，但大多数时候这些药物并不完全 根除肿瘤，留下未被初始治疗杀死的残留细胞。这些细胞 称为耐药持续细胞（DTPC），可以保持静止或临床上不可见， 并最终发展成为具有增强的抗性细胞 转移潜能在过去的十年里，我的实验室研究工作一直集中在 在很大程度上，阐明了EGFR酪氨酸激酶抑制剂（TKI）的耐药机制， 制定克服耐药性的战略，这些努力已经转化为新的药物， 和组合进入临床（例如泊齐替尼，Axl+EGFR抑制剂，VEGF+EGFR抑制剂， 等等）。Monique Nilsson博士一直在领导其中的一些研究，包括鉴定 应激激素和IL-6作为EGFR TKI耐药的驱动因素， 雅普/FOXM 1轴作为EGFR TKI耐药发展的关键途径。她还 鉴定了EGFR突变TKI抗性肿瘤如极光激酶的新靶点。更 最近，她能够在临床前证明VEGF的潜在机制， EGFR突变型肺肿瘤的依赖性。重要的是，尼尔森博士的研究导致了几个新的 目前正在我们机构进行的临床试验。为了防止出现 EGFR突变肿瘤的耐药性，Nilsson博士在这项提案中的目标是确定新的 在早期阶段消除DTPC的治疗策略。关于这一点，我们知之甚少。 DTPC的信号通路和潜在的治疗漏洞，我们的目的是进行一个 我的实验室在单细胞水平上对大量临床前模型进行了深入分析， 和尼尔森博士在过去几年里发展起来的我们相信，这些研究也将 有助于进一步了解其他分子定义的癌基因驱动的肺亚型 和其他实体瘤。