Studies on oncoprotein-induced feedback: Basic and therapeutic implications

癌蛋白诱导反馈的研究：基本和治疗意义

• 批准号: 9186828
• 负责人: NEAL ROSEN
• 金额: $ 102.84万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186828
• 关键词: Accounting; Alleles; Attenuated; Cell Death Induction; Cells; Clinical; Combined Modality Therapy; Data; Dependence; Development; Dose; Drug Targeting; FRAP1 gene; Feedback; Goals; Knowledge; Learning; Logic; MEKs; Methodology; Mutation; Nodal; Oncogenes; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Process; Property; Proteins; Proto-Oncogene Proteins c-akt; Receptor Activation; Schedule; Signal Pathway; Signal Transduction; Therapeutic; Work; actionable mutation; antitumor effect; base; cell transformation; epigenetic regulation; in vivo; inhibitor/antagonist; insight; mutant; novel; small hairpin RNA; success; tumor

PROJECT SUMMARY / ABSTRACT We have established that oncoproteins which function as dysregulated components of mitogenic signaling pathways cause marked feedback inhibition of physiologic signaling. Much of our recent work has focused on understanding the implications of this phenomenon. Insensitivity to feedback inhibition of receptor activation of wild type RAS is a common property of oncoproteins that activated ERK signaling that is required for them to elevate ERK output. Second, elevated pathway output includes elevated feedback inhibition of physiologic signaling pathways. This is a major determinant of the so- called oncoprotein dependence of transformed cells. Third, feedback-dependent oncoprotein pathway dependence reduces the robustness of the cell and creates a selection for mutations that activate feedback-Inhibited pathways and restores robustness. This accounts for some of the secondary driver mutations identified in tumors. Finally, inhibitors of oncoprotein-activated signaling have significant antitumor activity, but also relieve feedback inhibition of physiologic mitogenic signaling pathways and cause their reactivation. This attenuates their antitumor activity and creates a logic for inhibiting key reactivated pathways in tumors exposed to inhibitors of oncoproteins. This strategy has had some early clinical success and has become a paradigm for the development of rational combination therapies. Despite these insights, we still know only few of the details of oncoprotein-induced feedback and its relief by targeted inhibitors. We do know that these details vary as a function of tumor lineage and which pathway component is mutationally activated. Moreover, the effects of relieving feedback also vary depending on which node of the pathway is pharmacologically inhibited. We now plan to comprehensively study feedback and its relief by nodal inhibitors, focusing on a few tumors and using both methodologies biased by previous knowledge of normal signaling and unbiased shRNA screens. We utilize selective inhibitors of PI3K, AKT, mTOR, RAF, MEK, ERK, and a novel allele-specific inhibitor of RAS and study both short- and long-term adaptation, to determine whether some of the effects of the latter are due to epigenetic regulation. The goal is to develop new effective combination therapies based on these data and on in vivo studies to determine dose schedules that optimize induction of cell death.

项目摘要 /摘要 我们已经确定，癌细胞蛋白的作用为促丝分裂的成分失调 信号通路会导致明显的反馈抑制生理信号传导。我们最近的大部分工作 专注于理解这种现象的含义。对反馈抑制不敏感 野生型Ras的受体激活是激活ERK的癌蛋白的常见特性 他们提高ERK输出所需的信号。其次，高途径输出包括 生理信号通路的反馈抑制升高。这是So-的主要决定因素 称为转化细胞的癌蛋白依赖性。第三，依赖反馈依赖性癌蛋白途径 依赖性降低了细胞的鲁棒性，并为激活的突变创建选择 反馈抑制途径并恢复鲁棒性。这说明了一些次要驱动程序 在肿瘤中鉴定出的突变。最后，癌蛋白激活信号的抑制剂具有显着 抗肿瘤活性，但也可以减轻对生理有丝分裂信号通路和的反馈抑制 引起他们的重新激活。这会减轻他们的抗肿瘤活动，并创建限制钥匙的逻辑 暴露于癌蛋白抑制剂的肿瘤中重新激活的途径。该策略已经很早就了 临床成功，并已成为发展理性组合疗法的范式。 尽管有这些见解，但我们仍然只知道癌素诱导的反馈及其的细节 有针对性抑制剂的缓解。我们确实知道这些细节随肿瘤谱系的函数而变化， 哪个途径成分被突变。此外，还可以缓解反馈的影响 根据药理抑制的途径节点的不同。我们现在计划 全面研究反馈及其淋巴结抑制剂的缓解，专注于一些肿瘤并使用 两种方法都因先前对正常信号传导和无偏的shRNA筛查的知识而偏见。 我们利用PI3K，AKT，MTOR，RAF，MEK，ERK的选择性抑制剂和新型等位基因特异性 RAS的抑制剂并研究短期和长期适应，以确定是否某些 后者的作用是由于表观遗传调节引起的。目标是开发新的有效组合 基于这些数据和体内研究的疗法，以确定优化的剂量时间表 诱导细胞死亡。