Project 2: Targeting the ERK Pathway in KRAS- and BRAF-Driven Lung Cancers

项目 2：针对 KRAS 和 BRAF 驱动的肺癌中的 ERK 通路

• 批准号: 10246297
• 负责人: NEAL ROSEN
• 金额: $ 29.04万
• 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/10246297
• 关键词: Alleles; BRAF gene; Biochemical; Biological; Biological Process; Biological Response Modifier Therapy; Biology; Cell Survival; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Data; Development; Drug resistance; Effectiveness; Exposure to; FGFR1 gene; Feedback; Funding; Genes; Goals; Growth; Human; In Vitro; KRAS2 gene; Lung; Lung Adenocarcinoma; Lung Neoplasms; MEK inhibition; MEKs; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Methods; Minority; Modeling; Mutation; Non-Small-Cell Lung Carcinoma; Oncoproteins; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphotransferases; Process; Proto-Oncogenes; RAS inhibition; Ras/Raf; Receptor Protein-Tyrosine Kinases; Regimen; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Treatment Protocols; Work; antitumor effect; base; clinical effect; dimer; effective therapy; falls; in vivo; inhibitor/antagonist; lung Carcinoma; monomer; mutant; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; preclinical development; prevent; resistance mechanism; targeted treatment; therapeutically effective; tumor; tumor growth

Lung P01 Competing (1/25/17) Project 2 (Rosen, PI) ABSTRACT This project is focused on the development of effective therapies for lung tumors driven by activation of the ERK signaling pathway, particularly those in which the pathway is driven by mutations in the KRAS or BRAF proto-oncogenes. These tumors are particularly difficult to treat, in part because there are no direct inhibitors of mutant KRAS or of dimer-dependent non-V600 BRAF mutations or fusions; in part because of adaptive resistance to RAF or MEK inhibitors, which is mediated by relief of ERK dependent feedback; in part because BRAF V600 tumors develop acquired resistance; and because of the toxicity of MEK inhibitors. In the last funding period we made material progress in overcoming these obstacles. We discovered that BRAF mutants fall into three functional classes based on their mechanism of activation; developed specific mechanism-based methods of inhibition of each class of mutant; identified novel equipotent inhibitors of RAF monomers and dimers for the treatment of Class 1 and 2 RAF mutants; identified MEK inhibitors with an enhanced ability to inhibit MEK driven by mutant RAS; and characterized and determined the mechanism of action of direct inhibitors of KRAS G12C, the most common mutant RAS allele in lung cancer. The goal of the proposal is to use these inhibitors to understand the role of each of these oncoproteins in lung cancer and pursue their preclinical development. Aim 1 concerns the use of the RAF dimer/monomer inhibitor to understand the role of Class 2 dimer-dependent BRAF mutants and to develop treatment regimens for Class 1 and 2 mutants. Aim 2 concerns the study of Class 3 BRAF mutants, the most common class in lung cancer, and exploits a novel mechanism for inhibiting their activity. Aim 3 concerns the preclinical development of the KRAS G12C inhibitor and its use to study the functional role of mutant RAS in lung cancer and the consequences of its inhibition. Inhibiting ERK signaling driven by any of the mutants is expected to relieve ERK-dependent feedback inhibition of signaling and contribute to adaptive resistance. In collaboration with RP4, we will undertake the study of this process for each of these methods of inhibiting RAS/RAF/MEK signaling, attempt to identify pathways required for tumor cell survival, and develop combination therapy on this basis.

肺 P01 竞争 (1/25/17) 项目 2（罗森，PI） 抽象的 该项目的重点是开发由激活的肺肿瘤驱动的有效疗法 ERK 信号通路，特别是由 KRAS 或 BRAF 突变驱动的信号通路 原癌基因。这些肿瘤特别难以治疗，部分原因是没有直接的抑制剂 突变的 KRAS 或二聚体依赖性非 V600 BRAF 突变或融合；部分是因为适应性 对 RAF 或 MEK 抑制剂的耐药性，这是通过 ERK 依赖性反馈的缓解来介导的；部分是因为 BRAF V600 肿瘤产生获得性耐药；并且由于 MEK 抑制剂的毒性。在最后 资助期间我们在克服这些障碍方面取得了实质性进展。我们发现 BRAF 突变体 根据其激活机制分为三个功能类别；制定了具体机制 抑制每一类突变体的方法；鉴定出 RAF 单体的新型等价抑制剂 用于治疗 1 类和 2 类 RAF 突变体的二聚体；鉴定出具有增强能力的 MEK 抑制剂 抑制突变 RAS 驱动的 MEK；并表征并确定了直接的作用机制 KRAS G12C（肺癌中最常见的突变 RAS 等位基因）的抑制剂。该提案的目标是 使用这些抑制剂来了解每种癌蛋白在肺癌中的作用并探究它们的作用 临床前开发。目标 1 涉及使用 RAF 二聚体/单体抑制剂来了解 2 类二聚体依赖性 BRAF 突变体，并为 1 类和 2 类突变体开发治疗方案。目标2 涉及 3 类 BRAF 突变体（肺癌中最常见的一类）的研究，并开发了一种新的方法 抑制其活性的机制。目标 3 涉及 KRAS G12C 抑制剂的临床前开发 及其用于研究突变 RAS 在肺癌中的功能作用及其抑制的后果。 抑制任何突变体驱动的 ERK 信号传导有望缓解 ERK 依赖性反馈抑制 信号传递并有助于适应性抵抗。我们将与 RP4 合作开展这方面的研究 抑制 RAS/RAF/MEK 信号传导的每种方法的过程，尝试确定所需的途径 肿瘤细胞的存活，并在此基础上发展联合治疗。