P1 - Molecular Mechanisms of KIT Signaling and Imatinib Resistance in GIST

P1 - GIST 中 KIT 信号传导和伊马替尼耐药的分子机制

• 批准号: 7976097
• 负责人: CRISTINA R ANTONESCU
• 金额: $ 124.89万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7976097
• 关键词: 1-Phosphatidylinositol 3-Kinase; Alleles; Basic Science; Binding; Biochemical; Candidate Disease Gene; Cell Culture Techniques; Cells; Childhood; Clinical; Deletion Mutation; Detection; Disease; Doctor of Philosophy; Drug resistance; Evaluation; Event; Gametogenesis; Gastrointestinal Stromal Tumors; Generations; Genes; Genetic; Genomics; Genotype; Guidelines; Hematopoiesis; Human; Hyperplasia; Imatinib; Imatinib mesylate; In complete remission; Inherited; Integrins; Intervention; Investigation; Knock-in Mouse; Modeling; Molecular; Molecular Conformation; Molecular Profiling; Mus; Mutagenesis; Mutation; Oncogenic; PDGFRA gene; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Pattern; Phosphotransferases; Proteins; RNA Sequences; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Resistance; Role; Screening procedure; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Site; Solid; Stable Disease; Syndrome; System; Testing; Therapeutic; Tumor Cell Line; Tyrosine Kinase Inhibitor; base; cancer therapy; drug sensitivity; gain of function mutation; gastrointestinal; genome-wide; high throughput screening; human FRAP1 protein; human PDGFA protein; in vivo; inhibitor/antagonist; interest; interstitial; kinase inhibitor; mouse genome; mouse model; mutant; nodal myocyte; novel; novel therapeutics; partial response; pre-clinical; prototype; resistance mechanism; therapeutic target; tool; treatment strategy; tumorigenesis

Gastrointestinal stromal tumors (GISTs) are driven by KIT receptor tyrosine kinase, and most have gain-offunction mutations In KIT or occasionally in PDGFRA. Imatinib, which inhibits KIT and PDGFRA, produces a partial response or stable disease in 80% of GIST patients, but complete response is rare. Moreover, about half of the patients who benefit from imatinib treatment eventually develop drug resistance, and few other treatments are available. A common mechanism of acquired resistance is second-site KIT mutations. We propose 4 overall objectives. (1) Use genomic approaches to identify alternative signaling pathways in GIST lacking KIT or PDGFRA mutations and in imatinib-resistant GIST lacking an Identifiable mechanism of resistance. Candidate genes will be validated and pathway analysis applied to identify potential targets for therapy. (2) Identify mutations that confer resistance to imatinib or to other kinase inhibitors so as to develop guidelines for genotype-tailored therapy. (3) Investigate novel pharmacological intervention strategies in vivo in the KitV558del/+ mouse, a model of imatinib-responsive GIST. (4) Develop imatinib-resistant mouse models and apply them for the evaluation of new treatment strategies for imatinibresistant GIST. The treatment strategies to be tested are second^generation tyrosine kinase inhibitors alone and In combination with inhibitors of downstream effectors of KIT, targeting PI 3-kinase, integrin, and STAT signaling. By elucidating the pathways active in imatinib-resistant GIST and by preclinical investigations, we aim to find new therapeutic options for patients with Imatinib-resistant GIST.

胃肠道间质瘤 (GIST) 由 KIT 受体酪氨酸激酶驱动，大多数具有功能获得性 KIT 突变或偶尔出现 PDGFRA 突变。伊马替尼可抑制 KIT 和 PDGFRA，产生 80% 的 GIST 患者部分缓解或病情稳定，但完全缓解的情况很少见。此外，关于 受益于伊马替尼治疗的一半患者最终会产生耐药性，而其他患者则很少 可以进行治疗。获得性耐药的一个常见机制是第二位点 KIT 突变。 我们提出4个总体目标。 (1) 使用基因组方法来识别替代信号传导 缺乏 KIT 或 PDGFRA 突变的 GIST 以及缺乏可识别的伊马替尼耐药 GIST 的通路 抵抗机制。将验证候选基因并应用途径分析来识别 治疗的潜在目标。 (2) 识别对伊马替尼或其他激酶产生耐药性的突变 抑制剂，以便制定基因型定制治疗的指南。 (3) 研究新药理 KitV558del/+ 小鼠（伊马替尼反应性 GIST 模型）的体内干预策略。 (4) 开发 伊马替尼耐药小鼠模型并应用于伊马替尼耐药新治疗策略的评估 要旨。待测试的治疗策略是单独使用第二代酪氨酸激酶抑制剂 与 KIT 下游效应子抑制剂联合，靶向 PI 3-激酶、整合素和 STAT 发信号。通过阐明伊马替尼耐药 GIST 中的活跃通路和临床前研究，我们 旨在为伊马替尼耐药的胃肠道间质瘤患者寻找新的治疗选择。