Non–small cell lung cancer (NSCLC) is characterized by genomic alterations, yet a targetable mutation has not been discovered in nearly half of all patients. Recent studies have identified amplification of RICTOR, an mTORC2-specific cofactor, as a novel actionable target in NSCLC. mTORC2 is one of two distinct mTOR complexes to sense environmental cues and regulate a variety of cellular processes, including cell growth, proliferation, and metabolism, all of which promote tumorigenesis when aberrantly regulated. Interestingly, other components of mTORC2 are not coamplified with RICTOR in human lung cancer, raising the question as to whether RICTOR amplification-induced changes are dependent on mTORC2 function. To model RICTOR amplification, we overexpressed Rictor using the Cas9 Synergistic Activation Mediator system. Overexpression of Rictor increased mTORC2 integrity and signaling, but at the expense of mTORC1, suggesting that overexpressed Rictor recruits common components away from mTORC1. Additionally, Rictor overexpression increases the proliferation and growth of NSCLC 3D cultures and tumors in vivo. Conversely, knockout of RICTOR leads to decreased mTORC2 formation and activity, but increased mTORC1 function. Because Rictor has mTOR-dependent and -independent functions, we also knocked out mLST8, a shared mTOR cofactor but is specifically required for mTORC2 function. Inducible loss of mLST8 in RICTOR-amplified NSCLC cells inhibited mTORC2 integrity and signaling, tumor cell proliferation, and tumor growth. Collectively, these data identify a mechanism for Rictor-driven tumor progression and provide further rationale for the development of an mTORC2-specific inhibitor. Implications: RICTOR amplification drives NSCLC proliferation through formation of mTORC2, suggesting mTORC2-specific inhibition could be a beneficial therapeutic option.

中文翻译：

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Rictor 扩增通过 mTORC2 的形成和激活（以牺牲 mTORC1 为代价）促进 NSCLC 细胞增殖


非小细胞肺癌（NSCLC）的特点是基因组改变，但在近一半的患者中尚未发现可靶向的突变。最近的研究已经确定 RICTOR（一种 mTORC2 特异性辅助因子）的扩增是 NSCLC 中的一个新的可操作靶点。 mTORC2 是两种不同的 mTOR 复合物之一，用于感知环境信号并调节各种细胞过程，包括细胞生长、增殖和代谢，所有这些过程在异常调节时都会促进肿瘤发生。有趣的是，在人类肺癌中，mTORC2 的其他成分并不与 RICTOR 共扩增，这就提出了 RICTOR 扩增引起的变化是否依赖于 mTORC2 功能的问题。为了模拟 RICTOR 扩增，我们使用 Cas9 协同激活介体系统过度表达 Rictor。 Rictor 的过度表达增加了 mTORC2 的完整性和信号传导，但以牺牲 mTORC1 为代价，这表明过度表达的 Rictor 招募了 mTORC1 之外的常见成分。此外，Rictor 过度表达会增加 NSCLC 3D 培养物和体内肿瘤的增殖和生长。相反，敲除 RICTOR 会导致 mTORC2 形成和活性减少，但 mTORC1 功能增加。由于 Rictor 具有 mTOR 依赖性和独立性功能，因此我们还敲除了 mLST8，这是一种共享的 mTOR 辅助因子，但它是 mTORC2 功能所特别需要的。 RICTOR 扩增的 NSCLC 细胞中 mLST8 的诱导缺失会抑制 mTORC2 完整性和信号传导、肿瘤细胞增殖和肿瘤生长。总的来说，这些数据确定了 Rictor 驱动的肿瘤进展的机制，并为开发 mTORC2 特异性抑制剂提供了进一步的理论依据。 意义：RICTOR 扩增通过 mTORC2 的形成驱动 NSCLC 增殖，表明 mTORC2 特异性抑制可能是一种有益的治疗选择。