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: 10247722
• 负责人: NEAL ROSEN
• 金额: $ 107.76万
• 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/10247722
• 关键词: Alleles; Attenuated; Cell Death Induction; Cells; Clinical; Combined Modality Therapy; Data; Dependence; Development; Dose; Drug Targeting; Exposure to; FRAP1 gene; Feedback; Goals; Knowledge; Learning; Logic; MEKs; Methodology; Mutation; Nodal; Oncogenes; Oncoproteins; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Process; Property; Proteins; Proto-Oncogene Proteins c-akt; Ras Inhibitor; Receptor Activation; Receptor Inhibition; Schedule; Signal Pathway; Signal Transduction; Therapeutic; Work; antitumor effect; base; cell transformation; driver mutation; 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.

项目总结/摘要 我们已经证实，作为促有丝分裂素的失调成分发挥功能的癌蛋白， 信号传导途径引起生理信号传导的显著反馈抑制。我们最近的大部分工作 致力于理解这一现象的含义。对反馈抑制不敏感 野生型RAS的受体激活是激活ERK的癌蛋白的共同特性 这是它们提高ERK输出所需的信号。第二，升高的通路输出包括 生理信号通路的反馈抑制升高。这是一个重要的决定因素， 被称为癌蛋白依赖性。第三，反馈依赖的癌蛋白通路 依赖性降低了细胞的健壮性，并产生了对激活细胞的突变的选择。 反馈抑制途径并恢复鲁棒性。这说明了一些次要驱动因素 在肿瘤中发现的突变。最后，癌蛋白激活信号的抑制剂具有显著的 抗肿瘤活性，而且还减轻生理性促有丝分裂信号传导途径的反馈抑制， 导致它们重新激活。这减弱了它们的抗肿瘤活性，并创造了一种逻辑， 在暴露于癌蛋白抑制剂的肿瘤中重新激活通路。这一战略在早期已经有了一些 临床成功，并已成为开发合理组合疗法的范例。 尽管有这些见解，我们仍然只知道癌蛋白诱导的反馈及其作用的一些细节。 通过靶向抑制剂缓解。我们知道这些细节随着肿瘤谱系的变化而变化， 该途径组分被突变激活。此外，缓解反馈的效果也 取决于通路的哪个节点被抑制。我们现在计划 全面研究反馈及其缓解节点抑制剂，重点放在少数肿瘤和使用 这两种方法都受到以前对正常信号传导的了解的影响，并进行了无偏倚的shRNA筛选。 我们利用PI 3 K、AKT、mTOR、RAF、MEK、ERK的选择性抑制剂和一种新的等位基因特异性抑制剂。 RAS抑制剂和研究短期和长期适应，以确定是否有一些 后者的影响是由于表观遗传调节。目标是开发新的有效组合 基于这些数据和体内研究的治疗，以确定优化 诱导细胞死亡。