Project 3: Mechanisms and Modulators of Sensitivity and Resistance to Kinase Inhibitors in Lung Cancer

项目3：肺癌激酶抑制剂敏感性和耐药性的机制和调节剂

• 批准号: 10246298
• 负责人: Christine M. Lovly
• 金额: $ 30.31万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246298
• 关键词: Biochemical; Biological Assay; Biopsy Specimen; Bypass; Cancer Biology; Cancer cell line; Cell Line; Cell model; Cells; Chimeric Proteins; Clinical; Clinical Trials; Collection; Data; Development; Disease Progression; Disease Resistance; Drug Targeting; Drug resistance; EGFR inhibition; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Evolution; FDA approved; Gefitinib; Generations; Genetic Screening; Genomic approach; Genomics; Goals; Knowledge; Lung Adenocarcinoma; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mutation; Patient-Focused Outcomes; Patients; Pharmacology; Phosphotransferases; Point Mutation; Pre-Clinical Model; Precision therapeutics; Progressive Disease; Protein Tyrosine Kinase; Protocols documentation; Recurrence; Resistance; Resistance development; Resources; Sampling; Sequential Treatment; Signal Transduction; Site; Small Interfering RNA; Techniques; Testing; Therapeutic; Time; Tyrosine Kinase Inhibitor; Up-Regulation; Work; YES1 gene; clinical development; clinically relevant; cohort; crizotinib; design; drug-sensitive; exome sequencing; experience; human tissue; improved; inhibitor/antagonist; innovation; insight; kinase inhibitor; lung Carcinoma; lung cancer cell; member; molecular subtypes; mutant; neoplastic cell; next generation; novel; pre-clinical; resistance mechanism; src-Family Kinases; standard of care; targeted treatment; therapeutic target; therapy outcome; therapy resistant; transcriptome sequencing; tumor

PROJECT SUMMARY Acquired resistance remains a significant obstacle to optimal therapeutic outcomes for patients with lung cancer. The long-term goals of project 3 are to elucidate mechanisms of acquired resistance to targeted therapies in lung cancer and to develop rational strategies to forestall/overcome resistance. During the past 5 years, we have successfully identified mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) and developed therapeutic strategies to overcome resistance mediated by the EGFR T790M `second-site' mutation. We participated in the characterization of the mutant-selective third-generation EGFR TKI, osimertinib, which was recently approved by the US FDA for treatment of patients with metastatic T790M-positive EGFR-mutant lung cancer after progression on EGFR TKI therapy. Unfortunately, acquired resistance to osimertinib has already emerged in patients. Here, we plan to build on our extensive experience to characterize osimertinib resistance, in both the first-line setting (i.e., in the absence of T790M) and in the second-line setting (i.e., in the presence of T790M), to parallel ongoing clinical trials. In addition, using knowledge gained from our studies of EGFR TKI resistance, we will continue to advance our studies of acquired resistance to ALK TKI therapy in ALK-rearranged lung cancer. Therapeutic targeting of ALK fusion proteins with the first-generation ALK TKI, crizotinib, has shown significant clinical activity but is limited by the development of resistant disease. Although `next generation' ALK TKIs, including ceritinib, alectinib, ensartinib, and lorlatinib can overcome resistance to crizotinib, resistance to these more potent ALK TKIs has already developed in patients. We will leverage our proven proficiency in defining resistance mechanisms combined with innovative techniques – including forward genetic screens and siRNA screens – as well as unique resources – including novel cell lines and tumor biopsy samples taken at the time of disease progression on TKI therapy – to enhance our understanding of therapeutic resistance mechanisms with the overall goal of delaying or overcoming TKI resistance in lung cancer.

项目概要 获得性耐药仍然是肺癌患者获得最佳治疗结果的重大障碍 癌症。项目3的长期目标是阐明针对目标的获得性耐药机制 肺癌的治疗方法并制定合理的策略来预防/克服耐药性。在过去的5年里 多年来，我们已经成功地确定了第一代和第二代获得性耐药的机制 EGFR 酪氨酸激酶抑制剂 (TKI) 并开发了克服耐药介导的治疗策略 EGFR T790M“第二位点”突变。我们参与了突变体选择性的表征 第三代EGFR TKI奥希替尼近期获得美国FDA批准用于患者治疗 EGFR TKI 治疗进展后出现转移性 T790M 阳性 EGFR 突变肺癌。 不幸的是，患者中已经出现了对奥西替尼的获得性耐药。在这里，我们计划在此基础上 我们在一线环境（即在 缺乏 T790M）和二线环境（即存在 T790M），以平行正在进行的临床 试验。此外，利用我们从 EGFR TKI 耐药性研究中获得的知识，我们将继续 推进我们对 ALK TKI 治疗在 ALK 重排肺癌中获得性耐药的研究。治疗性 第一代 ALK TKI 克唑替尼 (crizotinib) 靶向 ALK 融合蛋白已显示出显着的临床效果 活性，但受到抗药性疾病的发展的限制。尽管“下一代”ALK TKI，包括 色瑞替尼、艾乐替尼、恩沙替尼和劳拉替尼可以克服对克唑替尼的耐药性，对这些耐药性更多 强效 ALK TKI 已在患者中开发出来。我们将利用我们经过验证的能力来定义 耐药机制与创新技术相结合——包括正向遗传筛选和 siRNA 屏幕 - 以及独特的资源 - 包括当时采集的新细胞系和肿瘤活检样本 TKI 治疗的疾病进展——增强我们对治疗耐药机制的理解 总体目标是延迟或克服肺癌中的 TKI 耐药性。