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

项目摘要 铁凋亡是一种铁依赖性的非凋亡性细胞死亡，是由过量的脂质诱导的 过氧化作用我们和其他人以前的研究确定铁凋亡是一种天然的肿瘤抑制机制 并表明，铁凋亡失活，像凋亡失活，有助于肿瘤的发展。最近， 我们和其他人还表明，放射治疗（RT）可以有效地诱导铁凋亡，并建议铁凋亡， 诱导剂（FIN）可用于RT以克服辐射抗性。然而， 放射抗性中的铁凋亡以及在RT中靶向铁凋亡的确切癌症或遗传背景仍然是 大部分尚未开发。本申请旨在确定铁凋亡失活的机制， 有助于KEAP 1突变型肺癌细胞的放射抗性，并评估RT和FIN的组合 治疗KEAP 1突变肺癌。KEAP 1通常在肺癌中突变，并且KEAP 1突变的肺 肺癌中KEAP 1突变或缺陷稳定了NRF 2，并促进了癌症的发生。 NRF 2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心 假设（i）KEAP 1缺陷主要通过抑制铁凋亡促进辐射抗性，和KEAP 1 通过NRF 2转录靶点SLC 7A 11和其他未鉴定的下游靶点调节铁凋亡; 和（ii）组合RT和FIN，其抑制SLC 7A 11（或从LC 7A 11中鉴定的其他潜在的铁凋亡抑制剂）， 我们的研究）是克服KEAP 1突变型肺癌放射抗性的有效治疗策略 而不会对正常组织造成显著损伤。为了验证我们的假设，我们将继续以下工作： 具体目标：具体目标1：确定KEAP 1调节铁凋亡的机制， 肺癌细胞的辐射抗性。具体目标2。确定FIN与RT相结合的有效性 用于治疗KEAP 1突变型肺癌。我们提出的研究有望确定新的机制， 铁下垂和辐射抵抗，并确定克服辐射抵抗的有效新治疗策略 肺癌的治疗。我们提出的研究将对我们理解 铁凋亡和辐射生物学的基本机制以及我们针对铁凋亡相关的能力 抗辐射治疗癌症。

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.