Decoding and targeting the PI3K-mTOR signaling network in cancer

 描述（由申请人提供）：解码和靶向癌症中的PI 3 K-mTOR信号传导网络正常细胞中的主要生长因子信号传导途径（例如，PI 3 K和RAS）也是癌细胞中最常被基因激活的，导致细胞自主生长和增殖。mTOR复合物1（mTORC 1）是细胞生长的主要驱动因素，在大多数人类癌症中被异常激活。这种激活通过上游癌基因和肿瘤抑制因子的网络发生，这些基因和肿瘤抑制因子聚集在mTORC 1上游的一个小G蛋白开关上。这种开关涉及结节性硬化症复合体（TSC）肿瘤抑制因子，它形成一种蛋白质复合体（TSC复合体），调节GTP酶Ras家族的一个成员，称为Rheb，是mTORC 1的一种必需的直接激活剂。我们前期的研究发现TSC复合物和Rheb是PI 3 K通路和mTORC 1信号通路之间的关键分子联系。在过去的十年中，我们的实验室一直处于PI 3 K-mTOR信号网络及其在正常细胞生理学和肿瘤细胞异常生长中的作用的重大发现的最前沿。该资助的重点是定义TSC复合物和mTORC 1上游致癌信号网络的复杂布线，以及人类癌症中该网络常见失调的下游后果。该研究计划基于我们过去5年在两个主要领域的突破性发现：1）上游信号传导-确定TSC-Rheb-mTORC 1回路的分子调控作为多个致癌信号传导通路的共享靶标，以及其在对作用于这些上游通路的靶向治疗药物产生耐药性中的作用; 2）下游后果-描述由PI 3 K-mTOR途径控制的关键代谢和适应性反应过程，其是癌细胞不受控制的生长和存活的基础，以及由操纵这些过程产生的治疗机会。这些集体研究强调需要深入了解这种无处不在的信号网络的分子布线以及它如何与关键细胞过程相互作用，以揭示可用于选择性杀死癌细胞的新漏洞，其中大多数在该网络的控制中表现出扰动。

 DESCRIPTION (provided by applicant): Decoding and targeting the PI3K-mTOR signaling network in cancer The major growth factor signaling pathways in normal cells (e.g., PI3K and RAS) are also the ones that are most frequently genetically activated in cancer cells, leading to cell autonomous growth and proliferation. mTOR complex 1 (mTORC1) is a major driver of cell growth and is aberrantly activated in the majority of human cancers. This activation occurs through a network of upstream oncogenes and tumor suppressors that converge on a small G protein switch directly upstream of mTORC1. This switch involves the tuberous sclerosis complex (TSC) tumor suppressors, which form a protein complex (the TSC complex) that regulates a member of the Ras family of GTPases, called Rheb, an essential direct activator of mTORC1. Our previous studies have found that the TSC complex and Rheb serve as the key molecular link between the PI3K pathway and mTORC1 signaling. Over the past decade, our laboratory has been at the forefront of major discoveries regarding the PI3K-mTOR signaling network and its role in both normal cellular physiology and the aberrant growth of tumor cells. This grant is focused on defining the complex wiring of the oncogenic signaling network upstream of the TSC complex and mTORC1 and the downstream consequences stemming from the common dysregulation of this network in human cancers. The research plan builds on our breakthrough findings from the past 5 years in two major areas: 1) Upstream signaling - To define the molecular regulation of the TSC- Rheb-mTORC1 circuit as a shared target of multiple oncogenic signaling pathways and its role in the development of resistance to targeted therapeutics acting on these upstream pathways; 2) Downstream consequences - To delineate the critical metabolic and adaptive response processes controlled by the PI3K- mTOR pathway that underlie the uncontrolled growth and survival of cancer cells and therapeutic opportunities arising from manipulation of these processes. These collective studies emphasize the need to gain a deep understanding of the molecular wiring of this ubiquitous signaling network and how it interfaces with key cellular processes in order to reveal novel vulnerabilities that can be exploited to selectively kill cancer cells, the majority of which exhibit perturbations in the contol of this network.