Translation addiction and targeting in colon cancer

摘要 结直肠癌(CRC)是美国和全世界癌症死亡的主要原因，其 Wnt、RAS/RAF/ERK和PI3K/AKT/mTOR信号的突变激活推动了细胞的发育。然而， 在CRC中，以个人司机为目标的成功有限。WNT、mTOR和ERK信号融合解除管制 EIF4F和Lead翻译包括c-Myc在内的关键致癌靶点。有趣的是，磷酸化的eIF4E(S209， 或p-eIF4E)对于开发或全局翻译是可有可无的，但对于转换和优化是必需的 某些模型中的肿瘤发生。P-eIF4E在人类癌症中升高的潜在原因及意义 致癌基因的翻译在很大程度上仍然未知。我们新的初步数据和最近的出版物支持 P-eIF4E在人和小鼠结肠癌发生和调节结肠癌中的关键作用 通过ATF4介导的代谢和应激适应的增殖。EIF4E/4F的药理学靶向性研究 在培养和体内诱导内质网应激和CRC细胞死亡。的核心假说 项目是磷酸化的eIF4E通过依赖ATF4来驱动结肠癌的发生和发展 新陈代谢和压力重新编程，并作为一种可操作和可用药的脆弱性。我们将对此进行测试 三个具体目标的假设。SA1.明确eIF4E磷酸化在结肠癌发生中的作用。 SA2.阐明p-eIF4E依赖的结肠癌发生机制。SA3.目标eIF4F/4E输入 结肠癌治疗。拟议的工作将开发和使用创新工具，包括磷酸化。 有缺陷的eIF4E癌细胞和小鼠，临床样本，以及高度机械性和综合性的方法 明确p-eIF4E在结肠癌生物学和治疗中的作用。如果成功，我们的工作将提供更好的 理解保护性应激和代谢适应中的致癌基因翻译，以及应对策略 针对这种上瘾进行治疗。这些发现可能对其他癌症的治疗具有重要意义。 过度活跃的WNT和RAS/RAF，目前还没有有效的治疗方法。

Summary Colorectal cancer (CRC) represents a leading cause of cancer death in the US and worldwide, and its development is driven by mutational activation of Wnt, RAS/RAF/ERK and PI3K/AKT/mTOR signaling. However, targeting individual driver in CRC has limited success. Wnt, mTOR and ERK signaling converges to deregulate eIF4F and lead to translate key oncogenic targets including c-Myc. Interestingly, phosphorylated eIF4E (S209, or p-eIF4E) is dispensable for development or global translation, but required for transformation and optimal tumorigenesis in some models. The underlying causes and significance of elevated p-eIF4E in human cancer and oncogenic translation remains largely unknown. Our novel preliminary data and recent publications supports a critical role of p-eIF4E in human and mouse colon cancer development, and in regulating colon cancer proliferation via ATF4-mediated metabolic and stress adaptation. Pharmacological targeting of eIF4E/4F induces endoplasmic reticulum stress and CRC cell death in culture and in vivo. The central hypothesis of the project is that phosphorylated eIF4E drives colon cancer initiation and progression through ATF4-dependent metabolic and stress reprogramming and serves as an actionable and druggable vulnerability. We will test this hypothesis in three specific Aims. SA1. Define the role of eiF4E phosphorylation in colon cancer development. SA2. Elucidate the mechanisms of p-eIF4E-dependent oncogenesis in colon cancer. SA3. Target eIF4F/4E in colon cancer therapy. The proposed work will develop and employ innovative tools, including phosphorylation defective eIF4E cancer cells and mice, clinical samples, and highly mechanistic and comprehensive approaches to define the role of p-eIF4E in colon cancer biology and therapy. If successful, our work will provide a better understanding of oncogenic translation in protective stress and metabolic adaptation, as well as strategies to target this addiction for therapy. These findings will likely have important implications in treating other cancers with hyperactive Wnt and RAS/RAF for which no effective therapy currently exists.