Targeting ferroptosis in radioresistance in lung cancer: mechanisms and preclinical translation

项目摘要 铁下垂是一种铁依赖的非凋亡性细胞死亡形式，由过多的脂质引起。 过氧化。我们和其他人之前的研究发现，铁下垂是一种自然的肿瘤抑制机制 研究表明，铁下垂失活，就像细胞凋亡失活一样，有助于肿瘤的发展。最近， 我们和其他人还表明，放射治疗(RT)可以有效地诱导铁性下垂，并提示铁性下垂 在RT中可以使用诱导剂(FINS)来克服辐射抵抗。然而，潜在的机制是 放射抵抗中的铁下垂与RT STEST中靶向铁下垂的确切癌症或遗传背景 很大程度上仍未被勘探。这项应用旨在确定铁下垂失活的机制 促进Keap1突变肺癌细胞的辐射抗性并评估RT和FINS的联合应用 治疗Keap1基因突变的肺癌。Keap1在肺癌中常见突变，Keap1突变肺 癌症对RT具有抗药性。肺癌中Keap1突变或缺失稳定NRF2并促进 NRF2介导的抗氧化反应。我们最近的出版物和新的初步数据支持我们的中央 假设：(1)Keap1缺乏主要通过抑制铁下垂来增强辐射抗性，而Keap1 通过NRF2转录靶点SLC7A11和其他未知的下游靶点调节铁下垂； 和(Ii)结合RT和FINS，使SLC7A11(或其他潜在的铁下垂抑制剂)失活 我们的研究)是克服Keap1突变肺癌放射抵抗的有效治疗策略 而不会对正常组织造成重大损害。为了验证我们的假设，我们将进行以下工作 具体目标：具体目标1：确定Keap1调节铁性下垂和 肺癌细胞的辐射抗性。具体目标2.确定FINS与RT相结合的有效性 用于治疗Keap1突变肺癌。我们提议的研究有望确定新的机制 铁性下垂和放射抵抗，并寻找有效的治疗策略来克服放射抵抗 在肺癌治疗方面。我们建议的研究将对我们对 铁性下垂的基本机制和放射生物学以及我们靶向铁性下垂的能力 癌症治疗中的辐射抵抗。

Project Summary Ferroptosis is an iron-dependent form of nonapoptotic cell death that is induced by excessive lipid peroxidation. Previous studies by us and others identified ferroptosis as a natural tumor suppression mechanism and showed that ferroptosis inactivation, like apoptosis inactivation, contributes to tumor development. Recently, we and others also showed that radiotherapy (RT) can potently induce ferroptosis and suggested that ferroptosis inducers (FINs) can be used in RT to overcome radioresistance. However, the underlying mechanisms of ferroptosis in radioresistance and the exact cancer or genetic contexts in which to target ferroptosis in RT still remain largely unexplored. This application aims to determine the mechanisms by which ferroptosis inactivation contributes to radioresistance in KEAP1-mutant lung cancer cells and to assess the combination of RT and FINs in treating KEAP1-mutant lung cancers. KEAP1 is commonly mutated in lung cancer, and KEAP1-mutant lung cancers are resistant to RT. KEAP1 mutation or deficiency in lung cancer stabilizes NRF2 and promotes an NRF2-mediated antioxidant response. Our recent publication and new preliminary data support our central hypotheses that (i) KEAP1 deficiency promotes radioresistance largely through inhibiting ferroptosis, and KEAP1 regulates ferroptosis through NRF2 transcriptional targets SLC7A11 and other unidentified downstream targets; and (ii) combining RT and FINs that inactivate SLC7A11 (or other potential ferroptosis inhibitors identified from our studies) is an effective therapeutic strategy to overcome radioresistance in KEAP1-mutant lung cancers without causing significant damage in normal tissues. To test our hypotheses, we will pursue the following specific aims: Specific Aim 1: To determine the mechanisms by which KEAP1 regulates ferroptosis and radioresistance in lung cancer cells. Specific Aim 2. To determine the effectiveness of combining FINs with RT for treating KEAP1-mutant lung cancer. Our proposed studies are expected to identify novel mechanisms of ferroptosis and radioresistance and to identify effective new therapeutic strategies to overcome radioresistance in lung cancer treatment. Our proposed studies will have a significant impact on both our understanding of the fundamental mechanisms of ferroptosis and radiation biology and our ability to target ferroptosis-related radioresistance in cancer treatment.