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/总结