Targeting Heme Metabolism for the Treatment of KRAS- KEAP1-Mutant Lung Adenocarcinoma

项目摘要 KRAS驱动的肺腺癌（LUAD）是一种主要的非小细胞肺癌（NSCLC） 治疗选择仍然有限的遗传亚型。KEAP 1/NRF 2信号通路中的突变 是几种实体癌（包括KRAS驱动的LUAD）中的常见事件，与不良患者相关 预后和结果。KEAP 1功能丧失（LOF）触发转录因子NRF 2的稳定 这会导致剧烈的代谢和抗氧化剂重编程， 肿瘤细胞的优势。然而，这些选择性优势也赋予了靶向代谢依赖性 其在KEAP 1/NRF 2突变的情况下特异性地出现。LUAD中这些突变的富集 携带未定义或不可针对的驱动突变尤其会暴露治疗漏洞 紧急确定KRAS突变LUAD内的代谢负债将使精确度的应用成为可能。 改善患者预后的药物。 在这个提议中，我提出的研究结果表明，Keap 1突变型肿瘤对 血红素合成的破坏和这种表型是由于Nrf 2激活。我概述了我提出的方法 来探究这种明显的脆弱性的代谢和遗传基础。然后我描述我将如何 评估该途径是否在Kras驱动的LUAD临床前模型中显示出靶向治疗的潜力，包括 使用LUAD的基因工程小鼠模型。 据报道，几乎所有血红素合成酶的亚晶突变都会导致某种形式的 遗传性肝卟啉症尽管这些疾病的潜在严重性，但它们在一般人群中的存在， 人群，包括健康成人，提供了血红素治疗窗口存在的证据 用于治疗癌症的合成抑制。这项奖学金申请旨在揭示一种新的代谢 靶向LUAD的这种遗传亚型，并将更好地理解一个基本的，但研究不足， 代谢途径在肺癌发展中的作用。

Project Abstract KRAS-driven lung adenocarcinoma (LUAD) represents a major non-small cell lung cancer (NSCLC) genetic subtype for which treatment options remain limited. Mutations in the KEAP1/NRF2 signaling pathway are common events in several solid cancers, including KRAS-driven LUAD, and are associated with poor patient prognosis and outcomes. KEAP1 loss of function (LOF) triggers stabilization of the transcription factor NRF2 which leads to dramatic metabolic and antioxidant reprogramming that confers proliferative and survival advantages to tumor cells. However, these selective advantages also confer targetable metabolic dependencies which arise specifically in the context of KEAP1/NRF2 mutations. The enrichment of these mutations in LUAD carrying undefined or untargetable driver mutations makes unmasking therapeutic vulnerabilities particularly urgent. Identifying metabolic liabilities within KRAS-mutant LUAD would enable the application of precision medicine for the improvement of patient outcomes. In this proposal, I present findings which suggest Keap1-mutant tumors show increased sensitivity to disruption of heme synthesis and that this phenotype is due to Nrf2 activation. I outline my proposed approach to interrogate the metabolic and genetic underpinnings of this apparent vulnerability. I then describe how I will assess if this pathway shows potential for targeted therapy in preclinical models of Kras-driven LUAD including the use of genetically engineered mouse models of LUAD. Hypomorphic mutations in nearly all heme synthesis enzymes have been reported to cause some form hereditary hepatic porphyria. Despite the potential severity of these diseases, their existence among the general population, including healthy adults, provides evidence for the existence of a therapeutic window for heme synthesis inhibition for the treatment of cancer. This fellowship application aims to uncover a novel metabolic target in this genetic subtype of LUAD and will yield a better understanding of a fundamental, yet understudied, metabolic pathway in the development of lung cancer.