The role of the RNA demethylase FTO in metabolic reprogramming of renal cell carcinoma

摘要 肾癌的患病率正在上升，是世界上最常见的十大癌症之一。清除单元格 肾细胞癌是最常见和侵袭性最强的肾癌。而主要的cccRCC 如果接受手术治疗，30%的患者被诊断为局部晚期或转移性疾病， 需要系统的治疗。尽管目前的治疗是针对肿瘤微环境的，但5年生存率 晚期慢性肾细胞癌的治愈率仍为11%。HIF-2在肾细胞癌中起重要的致癌作用，导致肾细胞癌的发生。 HIF-2抑制剂Belzutifan的最新进展。然而，先天和后天的抵抗力限制了耐久性。 在大多数患者中有反应。因此，有必要确定直接 抑制肾癌细胞的生长和存活。Von Hippel Lindau(VHL)肿瘤抑制基因是 在与VHL疾病相关的ccRCC肿瘤和90%的散发性ccRCC肿瘤中丢失。标志性特征 VHL缺陷的ccRCC包括低氧(HIF)信号的结构性激活、血管生成和代谢 重新编程。我们最近发现了RNA去甲基酶FTO和FTO之间的合成致死作用 CcRCC中的VHL。重要的是，FTO基因敲除降低了ccRCC的生长和生存，而不依赖于HIF-2。然而， 对1)FTO如何促进VHL缺陷的CCRCC生长和存活的可操作的机械论见解和2) 以FTO为基础的治疗在慢性肾细胞癌中的治疗潜力是这方面知识的关键空白。 申请。我们的中心假设是m6A RNA去甲基酶、脂肪质量和肥胖相关 蛋白质(FTO)，促进谷氨酰胺重新编程，以支持对Belzutifan敏感和 耐药的ccRCC。我们的具体目标将检验以下假设：(Aim1)FTO促进VHL缺陷 CCRCC通过m6A增加谷氨酰胺转运体SLC1A5的表达实现谷氨酰胺重编程 去甲基化；(目标2)FTO抑制剂在VHL缺陷性ccRCC中产生代谢脆弱性，可能是 用于治疗比祖替芬敏感和耐药的肿瘤。在结论中，我们将理解 CcRCC中m6A RNA甲基化和FTO作为谷氨酰胺重编程表位转录调节因子的作用。 这一贡献意义重大，因为它将确立SLC1A5，一种可操作和预测预后的癌症治疗方法 靶基因，由FTO通过m6A修饰进行调节。此外，对FTO机制的洞察- 介导的生长、存活和谷氨酰胺重编程对于精确度的快速翻译很重要 随着FTO抑制剂目前处于临床开发阶段，药物的研究也在不断深入。

Abstract Kidney cancer is increasing in prevalence and is one of the top 10 most common cancers world-wide. Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of kidney cancer. While primary ccRCC is treated with surgery, 30% of patients are diagnosed with regionally advanced or metastatic disease that requires systemic therapy. Despite current treatments that target the tumor microenvironment, the 5-year survival rate for advanced ccRCC remains 11%. HIF-2 plays an important oncogenic role in ccRCC, which has led to the recent development of the HIF-2 inhibitor belzutifan. However, innate and acquired resistance limits durable responses in the majority of patients. Thus, there is a need to identify additional therapeutic targets that directly inhibit the growth and survival of ccRCC cancer cells. The von Hippel Lindau (VHL) tumor suppressor gene is lost in ccRCC tumors associated with the VHL disease and in 90% of sporadic ccRCC tumors. Hallmark features of VHL deficient ccRCC include constitutive activation of hypoxic (HIF) signaling, angiogenesis and metabolic reprogramming. We recently discovered a synthetic lethal interaction between the RNA demethylase FTO and VHL in ccRCC. Importantly, FTO knockdown reduces ccRCC growth and survival independent of HIF-2. Yet, actionable mechanistic insights into 1) how FTO promotes VHL deficient ccRCC growth and survival and 2) the therapeutic potential of FTO-based therapy in ccRCC are critical gaps in knowledge addressed in this application. Our central hypothesis is that the m6A RNA demethylase, fat-mass and obesity-associated protein (FTO), promotes glutamine reprogramming to support the growth of belzutifan sensitive and resistant ccRCC. Our specific aims will test the following hypotheses: (Aim1) FTO promotes VHL deficient ccRCC glutamine reprogramming by increasing the expression of the glutamine transporter SLC1A5 via m6A demethylation; (Aim 2) FTO inhibitors create a metabolic vulnerability in VHL deficient ccRCC that can be exploited therapeutically to treat belzutifan sensitive and resistant tumors. Upon conclusion, we will understand the role of m6A RNA methylation and FTO as epitranscriptomic regulators of glutamine reprogramming in ccRCC. This contribution is significant since it will establish that SLC1A5, an actionable and prognostic cancer therapy target, is regulated by FTO through m6A modifications. Additionally, insight into the mechanisms of FTO- mediated growth, survival and glutamine reprogramming is important for the rapid translation of precision medicine approaches as FTO inhibitors are currently in clinical development.