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

肺P01竞争（1/25/17） 项目2（罗森，PI） 摘要 该项目的重点是开发有效的治疗肺肿瘤的方法， ERK信号传导途径，特别是其中该途径由KRAS或BRAF中的突变驱动的那些 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。 突变型KRAS或二聚体依赖性非V600 BRAF突变或融合;部分原因是适应性 对RAF或MEK抑制剂的抗性，这是由ERK依赖性反馈的缓解介导的;部分原因是 BRAF V600肿瘤产生获得性耐药性;并且由于MEK抑制剂的毒性。在过去 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;基于特定机制开发 抑制每类突变体的方法;鉴定RAF单体的新的等效抑制剂， 用于治疗1类和2类RAF突变体的二聚体;鉴定了MEK抑制剂， 抑制由突变RAS驱动的MEK;并表征和确定了直接 KRAS G12 C抑制剂，肺癌中最常见的突变RAS等位基因。该提案的目标是 使用这些抑制剂来了解这些癌蛋白中的每一种在肺癌中的作用， 临床前开发。目的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，并开发1类和2类突变体的治疗方案。目的2 涉及3类BRAF突变体的研究，这是肺癌中最常见的一类，并利用了一种新的 抑制其活性的机制。目的3涉及KRAS G12 C抑制剂的临床前开发 以及其在研究突变型RAS在肺癌中的功能作用及其抑制后果中的用途。 预期抑制由任何突变体驱动的ERK信号传导将减轻ERK依赖性反馈抑制 并有助于适应性抵抗。我们将与RP 4合作，研究这一问题。 这些抑制RAS/RAF/MEK信号传导的方法中的每一种的过程，试图鉴定所需的途径， 促进肿瘤细胞存活，并在此基础上开发联合治疗。

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.