Studies on oncoprotein-induced feedback: Basic and therapeutic implications

项目摘要/摘要 我们已经证实，作为有丝分裂的失调成分的癌蛋白 信号通路导致对生理信号的反馈抑制。我们最近的许多工作 专注于理解这一现象的影响。对反馈抑制不敏感 野生型RAS受体激活是激活ERK的癌蛋白的共同特性 提高ERK输出所需的信号。第二，提升的路径输出包括 增强了对生理信号通路的反馈抑制。这是一个主要的决定因素，所以- 称为转化细胞的癌蛋白依赖性。第三，反馈依赖的癌蛋白通路 依赖性降低了细胞的健壮性，并为激活的突变创建了一个选择 反馈抑制通路，恢复健壮性。这解释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物具有重要意义 抗肿瘤活性，但也解除反馈抑制的生理性有丝分裂信号通路和 导致它们重新激活。这减弱了它们的抗肿瘤活性，并创造了抑制KEY的逻辑 暴露于癌蛋白抑制剂的肿瘤中的重新激活的通路。这一战略已经有了一些早期的 临床上取得了成功，并已成为合理组合疗法发展的典范。 尽管有这些见解，我们仍然只知道很少的癌蛋白诱导的反馈和它的细节 靶向抑制剂的缓解作用。我们知道这些细节随着肿瘤谱系的不同而不同 哪一种途径成分被突变激活。此外，缓解反馈的效果也 根据路径的哪个节点被药物抑制而有所不同。我们现在计划 综合研究结节抑制药的反馈及其缓解作用，重点针对少数肿瘤并使用 这两种方法都受到先前对正常信号转导和无偏见shRNA筛选知识的偏见。 我们利用了PI3K、AKT、mTOR、RAF、MEK、ERK的选择性抑制剂和一种新的等位基因特异性的抑制剂 并对RAS的抑制剂进行短期和长期的适应研究，以确定一些 后者的影响是由于表观遗传调控。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方法，以确定优化的剂量计划 诱导细胞死亡。

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.