Decoding and Targeting the PI3K-mTOR Signaling Network in Cancer

摘要 正常细胞中的主要生长因子信号通路(如PI3K和RAS)也是 最常见的是在癌细胞中被基因激活，导致细胞自主生长和增殖。 MTOR复合体1(MTORC1)是这些通路的共同下游效应器，也是细胞的中枢驱动因子 并且在大多数人类癌症中被异常激活。此激活通过网络进行 上游癌基因和肿瘤抑制基因汇聚在一个小G蛋白开关上，直接位于 MTORC1.这种转换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 调节Ras家族GTP酶成员的复合体(TSC复合体)，称为Rheb，是一种必需的 MTORC1的直接激活剂。我们之前的研究发现，TSC复合体和Rheb是 PI3K通路和mTORC1信号之间的关键分子连接以及这种调节促进 正常细胞和癌细胞中支持细胞生长的关键代谢途径的变化。由 在过去的6年里，从这个R35的资金，我们有很大的推进和扩大这一领域的研究，开放 通过已公布的和正在进行的工作，建立了几个以前未预见到的新的调查途径。 利用这一机制提供的长期、稳定的资金，我们还开发了 创新的新遗传小鼠模型和方法，为我们带来新的突破性发现 在这笔赠款的下一个周期，特别是与PI3K-mTOR信号有关的情况下， 肿瘤微环境的营养和代谢生态位，这是这次更新的一个主要焦点。四 主要研究领域将包括定义A)生化和病理生理机制 在TSC复合体的调节和功能的基础上，B)mTORC1正确整合的能力 肿瘤微环境中的致癌和营养信号，C)PI3K的代谢结果- 不同来源、不同阶段和不同生态位肿瘤中mTOR的激活和抑制，以及D)靶向代谢 在肿瘤中伴随着其异常调控的脆弱性。虽然关于这一点的关键机械问题 无处不在的信令网络将继续通过严格的生物化学和细胞生物学得到回答 研究，我们的大部分努力将结合新的遗传模型和最先进的分析工具来定义 PI3K-mTOR网络在体内的显著特征，因为它们适用于肿瘤的新陈代谢、生长和 进步。我们研究的首要目标是定义该信令网络在 肿瘤和如何通过不受控制的mTORC1最好地针对高比例的肿瘤 信号传递，超越了mTOR抑制剂的单一药物使用。我相信，如果给予资源，我们将 继续加深对癌细胞生物学、肿瘤微环境和治疗的了解 脆弱性，同时也跳入了癌症研究的新的、目前不可预测的领域。

ABSTRACT 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 shared downstream effector of these pathways and a central 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 and that this regulation promotes changes in key metabolic pathways underlying cell growth in both normal and cancer cells. Supported by the last 6 years of funding from this R35, we have greatly advanced and expanded this area of research, opening up several previously unforeseen new avenues of investigation through both published and ongoing work. Taking advantage of the long-term, stable funding afforded by this mechanism, we have also developed innovative new genetic mouse models and methodologies that set us up for new breakthrough discoveries over the next cycle of this grant, especially related to PI3K-mTOR signaling within the poorly understood nutrient and metabolic niche of the tumor microenvironment, which is a major focus of this renewal. Four major areas of research will include defining A) the biochemical and pathophysiological mechanisms underlying the regulation and function of the TSC complex, B) the capacity of mTORC1 to properly integrate oncogenic and nutrient signals within the tumor microenvironment, C) the metabolic consequences of PI3K- mTOR activation and inhibition in tumors of different origins, stages, and niches, and D) targetable metabolic vulnerabilities accompanying its aberrant regulation in tumors. While key mechanistic questions regarding this ubiquitous signaling network will continue to be answered through rigorous biochemical and cell biological studies, much of our efforts will combine novel genetic models with state-of-the-art analytical tools to define the salient in vivo features of the PI3K-mTOR network as they apply to tumor metabolism, growth, and progression. The overarching goals of our research are to define the precise roles of this signaling network in cancer and how best to therapeutically target the high percentage of tumors with uncontrolled mTORC1 signaling, beyond the single-agent use of mTOR inhibitors. I am confident that, if given the resources, we will continue to gain a deeper understanding of cancer cell biology, the tumor microenvironment, and therapeutic vulnerabilities, while also making leaps into new, currently unpredictable domains of cancer research.