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

靶向肺癌放射抗性中的铁死亡：机制和临床前转化

• 批准号: 10117585
• 负责人: Boyi Gan
• 金额: $ 39.33万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-07 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10117585
• 关键词: Antioxidants; Apoptosis; CRISPR screen; Cell Death; Communities; Complement; Data; Development; Genetic; Genetic Transcription; Goals; Heart Injuries; Human; Immune system; Iron; Link; Lipid Peroxidation; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Medical; Mutate; Mutation; Normal tissue morphology; Outcome; Pathway interactions; Publications; Radiation therapy; Radiobiology; Resistance; Role; Testing; Translating; Translations; Tumor Biology; Tumor Suppression; cancer therapy; comparative; effectiveness evaluation; inhibitor/antagonist; innovation; lung cancer cell; mouse model; mutant; novel; novel therapeutic intervention; pre-clinical; radiation resistance; radiation-induced lung injury; radioresistant; refractory cancer; response; therapeutically effective; tumor; tumor growth

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.

项目概要 铁死亡是一种铁依赖性非凋亡细胞死亡形式，由过量脂质诱导 过氧化。我们和其他人之前的研究发现铁死亡是一种天然的肿瘤抑制机制 并表明铁死亡失活，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）可以有效诱导铁死亡，并表明铁死亡 诱导剂 (FIN) 可用于 RT 来克服放射抗性。然而，其根本机制 放射抗性中的铁死亡以及在 RT 中针对铁死亡的确切癌症或遗传背景 很大程度上仍未被探索。本申请旨在确定铁死亡失活的机制 有助于 KEAP1 突变肺癌细胞的放射抗性，并评估 RT 和 FIN 的组合 治疗 KEAP1 突变型肺癌。 KEAP1 在肺癌中常见突变，KEAP1 突变肺癌 癌症对放疗有抵抗力。肺癌中的 KEAP1 突变或缺陷可稳定 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 (i) KEAP1 缺乏主要通过抑制铁死亡来促进放射抗性，并且 KEAP1 通过 NRF2 转录靶标 SLC7A11 和其他未识别的下游靶标调节铁死亡； (ii) 结合 RT 和 FIN 来灭活 SLC7A11（或从 我们的研究）是克服 KEAP1 突变肺癌放射抗性的有效治疗策略 不会对正常组织造成明显损伤。为了检验我们的假设，我们将追求以下目标 具体目标：具体目标 1：确定 KEAP1 调节铁死亡的机制 肺癌细胞的放射抗性。具体目标 2. 确定 FIN 与 RT 结合的有效性 用于治疗 KEAP1 突变型肺癌。我们提出的研究预计将确定新的机制 铁死亡和放射抗性，并确定有效的新治疗策略来克服放射抗性 在肺癌治疗中。我们提出的研究将对我们的理解产生重大影响 铁死亡和放射生物学的基本机制以及我们针对铁死亡相关的能力 癌症治疗中的放射抗性。